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Muccio S, Hirtz C, Kramer D, Paris J, Descloux S, Fedeli O, Deiteren A, Tribula A, Lehmann S, Vialaret J. In-depth characterization and semi-quantification of anti-drug antibodies in clinical samples using specific hybrid IC-LC-MS/MS methods. Anal Biochem 2025; 701:115797. [PMID: 39921137 DOI: 10.1016/j.ab.2025.115797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/26/2025] [Accepted: 01/30/2025] [Indexed: 02/10/2025]
Abstract
Anti-drug antibodies (ADAs) generated by biotherapeutics can impair the drug clearance, prevent the binding to its target or lead to hypersensitivity reactions, thereby affecting efficacy and safety. It is therefore essential to assess the immunogenicity of potential biotherapeutics, particularly in clinical development. Ligand binding assays (LBA) are the gold standard for ADA detection because of their high sensitivity and throughput. However, LBA assays don't provide details on the isotypes produced and their relative abundance. As certain isotypes are known to be associated with ADA mediated adverse events, this information could be helpful to anticipate or better characterize the immunogenicity risk of biotherapeutics. A hybrid IC-LC-MS/MS strategy was developed for the detection of specific isotypes/subclasses of ADAs in a phase I clinical study. A first approach using the biotinylated drug to capture ADAs in human serum allowed the simultaneous semi-quantification of all IgG subclasses and the detection of ADAs of the IgM isotype in clinical samples. These results enabled a detailed characterization of the immune response against the biotherapeutic. A second assay was developed using a sequential immunocapture to measure drug specific IgEs known to be potentially associated with hypersensitivity reactions. The overall results were consistent with the clinical adverse events observed in some healthy volunteers.
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Affiliation(s)
- Stéphane Muccio
- Sanofi, TMED-BCB, 371 rue du Professeur Blayac, 34184 Montpellier, France.
| | - Christophe Hirtz
- Montpellier Univ, IRMB CHU, INM INSERM, 80 avenue Augustin Fliche, 34295 Montpellier, France
| | - Daniel Kramer
- Sanofi, TMED-BCB, Industriepark Höchst 65926 Frankfurt, Germany
| | - Johanna Paris
- Sanofi, TMED-BCB, 371 rue du Professeur Blayac, 34184 Montpellier, France
| | - Sandrine Descloux
- Sanofi, TMED-BCB, 371 rue du Professeur Blayac, 34184 Montpellier, France
| | - Olivier Fedeli
- Sanofi, TMED-BCB, 371 rue du Professeur Blayac, 34184 Montpellier, France
| | - Annemie Deiteren
- Ablynx R&D, TMED-TMCP, Technologiepark-Zwijnaarde 21, 9052 Gent/Zwijnaarde, Belgium
| | | | - Sylvain Lehmann
- Montpellier Univ, IRMB CHU, INM INSERM, 80 avenue Augustin Fliche, 34295 Montpellier, France.
| | - Jérôme Vialaret
- Montpellier Univ, IRMB CHU, INM INSERM, 80 avenue Augustin Fliche, 34295 Montpellier, France
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Ebbers HC, Taylor PC, Leng X, Wei W, Kinsella NM, Zhou Y, Yang X, Chamberlain P. A Comparison of the Immunogenicity of Intravenous BAT1806, a Tocilizumab Biosimilar, and Its Reference Product. Rheumatol Ther 2025; 12:529-546. [PMID: 40198544 PMCID: PMC12084431 DOI: 10.1007/s40744-025-00760-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/18/2025] [Indexed: 04/10/2025] Open
Abstract
INTRODUCTION Biosimilars need to demonstrate similarity in terms of quality, pharmacokinetics (PK), efficacy, safety, and immunogenicity. Here, we report the outcome of a comprehensive evaluation of the immunogenicity of the biosimilar BAT1806 compared with the tocilizumab reference product (TCZ). METHODS We conducted a post hoc analysis of study BAT1806-001-CR, a comparative PK study in healthy male volunteers (n = 129), and BAT1806-002-CR, a phase III, 52-week trial in patients with rheumatoid arthritis (n = 621). Anti-drug antibodies (ADA), ADA titers, and neutralizing ADA were measured, and their impact on PK, safety, and efficacy parameters were assessed. RESULTS In BAT1806-001-CR, treatment-induced ADA were observed in 37.8% of participants for the BAT1806 group, 28.6% for the EU-sourced TCZ group, and 31.0% for the US-sourced TCZ group, without an impact on PK and safety. In BAT1806-002-CR after 52 weeks, 28.2% of participants in the BAT1806 group developed treatment-induced ADA, compared with 24.0% in the TCZ group and 19.7% of participants who initiated TCZ and switched to BAT1806 at week 24. ADA-positive participants reported lower geometric mean serum tocilizumab trough concentrations than ADA-negative participants in all treatment groups. ADA-positive participants achieved similar efficacy outcomes to ADA-negative participants in all treatment groups. ADA were not associated with an incremental risk of treatment-emergent adverse events or hypersensitivity in any of the treatment groups. CONCLUSIONS The results of these post hoc analyses did not indicate any clinically relevant differences in the immunogenicity profile of intravenously administered BAT1806 compared with TCZ. TRIAL REGISTRATION ClinicalTrials.gov identifiers, NCT03606876, NCT03830203.
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Affiliation(s)
- Hans C Ebbers
- Biogen, Prins Mauritslaan 13-19, PO Box 42, 1170 AA, Badhoevedorp, The Netherlands.
| | - Peter C Taylor
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Xiaomei Leng
- Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Beijing, China
| | - Wei Wei
- Biogen International GmbH, Baar, Switzerland
| | | | - Yinbo Zhou
- Bio-Thera Solutions, Ltd, Guangzhou, China
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Gupta P, Srivastava A, Ryman JT, Swanson MD, Kozhich A, Jawa V, Meibohm B. Short-Term Immunosuppression in Rats Induces Prolonged Immune Tolerance Towards a Human Monoclonal Antibody, Erenumab. AAPS J 2025; 27:94. [PMID: 40379907 DOI: 10.1208/s12248-025-01083-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Accepted: 05/01/2025] [Indexed: 05/19/2025] Open
Abstract
Administration of human therapeutic proteins such as monoclonal antibodies (mAb) to animals during preclinical drug development often leads to the development of anti-drug antibodies (ADA). ADA may reduce the systemic exposure of the mAb by enhancing its immune-complex mediated clearance. Thus, ADA may hinder the preclinical pharmacokinetic and toxicology assessments of mAbs. To mitigate this effect, we explored the ability of short-term administration of immunosuppressants to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. In two studies, we investigated dosing regimens using the immunosuppressants methotrexate and tacrolimus/sirolimus combination, and compared them to non-immunosuppressed control groups. Each study comprised three phases: induction (weeks 1-4), washout (weeks 5-8), and rechallenge (weeks 9-12). Animals received mAb during the induction and rechallenge phase, while immunosuppression was limited to the induction and washout phase. Blood samples were collected at predefined time-points for erenumab and ADA quantification. The tacrolimus/sirolimus regimen, but not the tested methotrexate regimens, completely prevented ADA formation in all treated animals relative to the control groups. The tacrolimus/sirolimus treated animals not only remained ADA-negative with initial immunosuppression during the induction phase but remained ADA-negative even after erenumab rechallenge suggesting the induction of immune-tolerance beyond the immunosuppressive treatment period. Correspondingly, erenumab systemic exposures were maintained throughout the study period in all animals in the tacrolimus/sirolimus group and were similar to the erenumab exposures in ADA-negative animals of the control group. In contrast, ADA-positive animals in the control group exhibited a 60-80% reduction in erenumab exposures.
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Affiliation(s)
- Paridhi Gupta
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A
| | - Ashish Srivastava
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A
| | - Josiah T Ryman
- Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Rahway, New Jersey, U.S.A
| | - Michael D Swanson
- Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., West Point, Pennsylvania, U.S.A
| | - Alexander Kozhich
- Clinical Pharmacology, Pharmacometrics & Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey, U.S.A
| | - Vibha Jawa
- Clinical Pharmacology, Pharmacometrics & Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey, U.S.A
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, U.S.A..
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, 881 Madison Avenue, Suite 435, Memphis, Tennessee, 38163, U.S.A..
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Jarab AS, Abu Heshmeh SR, Al Meslamani AZ. Biosimilars and immunogenicity: a matter of concern? Expert Opin Drug Saf 2025; 24:519-527. [PMID: 39955621 DOI: 10.1080/14740338.2025.2467817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 01/29/2025] [Indexed: 02/17/2025]
Abstract
INTRODUCTION Biosimilars have transformed treatment modalities across various medical fields such as oncology, rheumatology, and immunology. Despite their potential for reducing healthcare costs, concerns persist regarding their ability to induce an immune response, which could affect efficacy and safety. This review critically evaluates the current evidence on the immunogenicity of biosimilars and discusses the regulatory frameworks guiding their approval and monitoring. AREAS COVERED This review includes studies from databases like Scopus, PubMed, Web of Science, and ScienceDirect, published up to April 2024. It explores the 'totality of the evidence' approach used by regulatory bodies like the FDA and EMA, detailing analytical, preclinical, and clinical assessments that ensure biosimilars' similarity to their reference products in terms of structure, function, and clinical outcomes. The review also addresses the challenges and limitations in current research methodologies and the implications of immunogenicity on therapeutic efficacy and patient safety. EXPERT OPINION While substantial evidence confirms the safety and efficacy of biosimilars, the review emphasizes the need for continuous regulatory vigilance and advanced methodologies in post-marketing surveillance to capture long-term immunogenicity data effectively. It advocates for integrating cutting-edge analytical techniques and personalized medicine to better manage immunogenic risks associated with biological therapies.
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Affiliation(s)
- Anan S Jarab
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Shrouq R Abu Heshmeh
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Ahmad Z Al Meslamani
- College of Pharmacy, Al Ain University, Abu Dhabi, United Arab Emirates
- AAU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
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Chen F, He X, Mao Y, Coble K. Method development for the detection of anti-drug antibodies against a therapeutic peptide: assay format selection. Bioanalysis 2025; 17:537-548. [PMID: 40346877 DOI: 10.1080/17576180.2025.2501937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 05/01/2025] [Indexed: 05/12/2025] Open
Abstract
AIM Monitoring immune responses to therapeutic peptides with endogenous counterparts is crucial for evaluating drug safety and efficacy. In this paper, we focused on the selection of an optimal assay format to develop a sensitive, robust, and drug-tolerant immunoassay for the detection of anti-drug antibody (ADA) against a therapeutic peptide. RESULTS We assessed distinct ADA assay formats for preclinical and clinical studies, such as direct binding with labeled protein A/G, direct binding with labeled multiple species-specific antibodies for detection, bridging and affinity capture elution (ACE) formats. The assay formats were evaluated based on multiple assay parameters including sensitivity, drug tolerance, individual matrix variability and inter-assay precision. Overall, direct binding assay with labeled protein A/G for detection, which utilized less labeled peptide drug and achieved desired sensitivity and drug tolerance, is appropriate for preclinical studies. Bridging assay is more suitable format to support clinical studies as bridging assay has less assay variability than ACE assay. CONCLUSION This study highlighted advantages and limitations of each ADA assay format for peptide drugs and evaluated the performance of different assay formats in the assay development process to aid in the selection of the best fit-for-purpose assay formats for preclinical and clinical phases.
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Affiliation(s)
- Fangfang Chen
- Bioanalytical Sciences, DMPK, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Xiaolong He
- Bioanalytical Sciences, DMPK, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Yan Mao
- Bioanalytical Sciences, DMPK, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
| | - Kelly Coble
- Bioanalytical Sciences, DMPK, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
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Shi P, Wang Z, Sheng W, Wang Z, Wang S, Zhang C, Zhao L, Zou J, Zhou H. Whole-canine neutralizing antibodies generated by single B cell antibody technology elicit therapeutic protection against canine distemper virus infection. Vet Microbiol 2025; 302:110412. [PMID: 39893954 DOI: 10.1016/j.vetmic.2025.110412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 02/04/2025]
Abstract
Canine distemper virus (CDV) causes a highly contagious and fatal disease in domestic and wild carnivores. Currently, vaccination is the primary method for preventing canine distemper. However, incidents of vaccine immunization failures continue to be reported. There are no specific and effective treatment agents available for canine distemper infection. Neutralizing antibodies offer a potential approach for the treatment of viral diseases. In this study, single B cell antibody technology was applied to obtain whole-canine antibodies against CDV. 7 monoclonal antibodies were screened and showed high binding affinity to CDV hemagglutinin (H) protein, with D16 and F53 exhibited high specificity and neutralizing activity against CDV. Furthermore, D16 exhibited effective therapeutic potential in dogs subjected to lethal dose CDV attacks in vivo. In conclusion, our study offers an alternative approach for acquiring neutralizing antibody and provides a promising new strategy for the treatment of CDV infection.
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Affiliation(s)
- Pengfei Shi
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Zhihao Wang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Wei Sheng
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Zhichen Wang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Sheng Wang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Chengguang Zhang
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China
| | - Ling Zhao
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, Hubei, PR China; Hubei Hongshan Laboratory, Wuhan, Hubei, PR China
| | - Jiahui Zou
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China.
| | - Hongbo Zhou
- National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, PR China; Department of Animal Science, Tibet Agricultural and Animal Husbandry College, Nyingchi, Tibet, PR China; Frontiers Science Center for Animal Breeding and Sustainable Production, Wuhan, Hubei, PR China; Hubei Hongshan Laboratory, Wuhan, Hubei, PR China.
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7
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Elliott RJ, Pourmohamad T, Webb-Vargas Y, Yan W, Nijem I, Siguenza P, Song Y. Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays. AAPS J 2024; 27:19. [PMID: 39702644 DOI: 10.1208/s12248-024-00999-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 11/16/2024] [Indexed: 12/21/2024] Open
Abstract
Per FDA guidance, method comparability should be established if an anti-drug antibody (ADA) assay is run by two or more independent laboratories during a study. Genentech, Inc. is evaluating an immunogenicity risk-based comparability approach consisting of both technical and clinical aspects. Technical comparability of the relative sensitivity (RS) is assessed using the Two One-Sided T-tests (TOST) statistical analysis which evaluates if the difference (in absolute value) of the RS means of the two laboratories is less than a pre-specified level of comparability, the practically significant difference (PSD). Clinical comparability is based on the molecule's immunogenicity risk. A basic and in-depth assessment for low and high-risk molecules are used, respectively. An alternative strategy for molecules with limited incurred sample availability is to be used. In the basic assessment, samples are either unfortified or fortified with surrogate ADA positive control at method appropriate concentrations in a representative biological matrix. Acceptable comparability requires in both methods i) at least 80% of the unfortified samples screen and confirm negative, ii) at least 90% of the low concentration samples screen and confirm positive; and iii) 100% of the high concentration samples screen and confirm positive. The in-depth assessment uses at least 100 incurred samples from 30 or more ADA-positive and ADA-negative patients. The results are evaluated using a 2 by 2-confusion matrix and Cohen's Kappa score where 1 indicates perfect agreement. Acceptable comparability requires a Cohen's Kappa score of greater than 0.40. This strategy allows for a robust technical and clinical method comparability assessment.
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Affiliation(s)
- R J Elliott
- Bioanalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA.
| | - T Pourmohamad
- PD Data and Statistical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - Y Webb-Vargas
- Product Development Data Sciences-Nonclinical Biostatistics, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - W Yan
- Bioanalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - I Nijem
- Bioanalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - P Siguenza
- Bioanalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
| | - Y Song
- Bioanalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, California, 94080, USA
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Reinert T, Houzé P, Mignet N, Naghizade A, Alez-Martin L, Hernandez-Alba O, Leclerc A, Cianferani S, Gahoual R, Francois YN. Therapeutic Monoclonal Antibody─Antidrug Antibody Affinity Constant Determination Using Capillary Electrophoresis-Tandem Mass Spectrometry. Anal Chem 2024; 96:19286-19293. [PMID: 39600236 DOI: 10.1021/acs.analchem.4c02932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Monoclonal antibody (mAbs) therapeutics cannot evade the occurrence of adverse effects. Thus, mAbs are commonly triggering immune responses corresponding to the expression of antidrug antibodies. Antidrug antibodies can neutralize mAbs, leading to their inhibition and hasten clearance, which dramatically hampers their therapeutic effects. Therefore, studies concerning the affinity between a mAbs and the corresponding antidrug antibody are demonstrating a growing interest to further understand the outcome of biotherapeutics after administration. We describe a novel analytical approach for the determination of the dissociation constant (Kd) between a mAb and an antidrug antibody using capillary electrophoresis coupled to mass spectrometry (CE-MS/MS). The CE-MS/MS method employs a competitive assay, followed by the quantification of the residual amount of the active mAbs. The methodology allowed for the measurement of Kd using serum samples without the implementation of immobilization to achieve protein-protein interaction. This characteristic enabled us to generate the interaction in conditions reflecting the physiological environment. A mathematical treatment was developed to calculate Kd from MS/MS data, taking into account the stoichiometry of the mAbs/antidrug antibody complex and the bivalent properties of the two immunoglobulins. Prior to CE-MS/MS analysis, the interaction of the two proteins was studied by using mass photometry (MP) to determine equilibrium conditions and complexation stoichiometry. CE-MS/MS was used to investigate the interaction between infliximab and a neutralizing anti-infliximab antibody. Results allowed to measure a Kd of 14.4 ± 2.9 nM. MS instrumentation sensitivity and specificity showed to be relevant to achieve accurate and robust Kd measurements for strong interactions in the nanomolar range.
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Affiliation(s)
- Tessa Reinert
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS), Université de Strasbourg, CNRS UMR7140, CMC, Strasbourg 67081, France
- Université Paris Cité CNRS, Inserm, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), Faculté de Sciences Pharmaceutiques et Biologiques, Paris 75270, France
| | - Pascal Houzé
- Université Paris Cité CNRS, Inserm, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), Faculté de Sciences Pharmaceutiques et Biologiques, Paris 75270, France
- Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris 75010, France
| | - Nathalie Mignet
- Université Paris Cité CNRS, Inserm, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), Faculté de Sciences Pharmaceutiques et Biologiques, Paris 75270, France
| | - Aynur Naghizade
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS), Université de Strasbourg, CNRS UMR7140, CMC, Strasbourg 67081, France
| | - Lola Alez-Martin
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS), Université de Strasbourg, CNRS UMR7140, CMC, Strasbourg 67081, France
| | - Oscar Hernandez-Alba
- Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, CNRS UMR7178, IPHC, Strasbourg 67037, France
- Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg 67087, France
| | - Armand Leclerc
- Centre de Recherche Astrophysique de Lyon (CRAL), Université Lyon 1, CNRS, UMR5574, ENS de Lyon, Saint-Genis-Laval, Lyon 69007, France
| | - Sarah Cianferani
- Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, CNRS UMR7178, IPHC, Strasbourg 67037, France
- Infrastructure Nationale de Protéomique ProFI - FR2048, Strasbourg 67087, France
| | - Rabah Gahoual
- Université Paris Cité CNRS, Inserm, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS), Faculté de Sciences Pharmaceutiques et Biologiques, Paris 75270, France
| | - Yannis-Nicolas Francois
- Laboratoire de Spectrométrie de Masse des Interactions et des Systèmes (LSMIS), Université de Strasbourg, CNRS UMR7140, CMC, Strasbourg 67081, France
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Carter PJ, Quarmby V. Immunogenicity risk assessment and mitigation for engineered antibody and protein therapeutics. Nat Rev Drug Discov 2024; 23:898-913. [PMID: 39424922 DOI: 10.1038/s41573-024-01051-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/21/2024]
Abstract
Remarkable progress has been made in recent decades in engineering antibodies and other protein therapeutics, including enhancements to existing functions as well as the advent of novel molecules that confer biological activities previously unknown in nature. These protein therapeutics have brought major benefits to patients across multiple areas of medicine. One major ongoing challenge is that protein therapeutics can elicit unwanted immune responses (immunogenicity) in treated patients, including the generation of anti-drug antibodies. In rare and unpredictable cases, anti-drug antibodies can seriously compromise therapeutic safety and/or efficacy. Systematic deconvolution of this immunogenicity problem is confounded by the complexity of its many contributing factors and the inherent limitations of available experimental and computational methods. Nevertheless, continued progress with the assessment and mitigation of immunogenicity risk at the preclinical stage has the potential to reduce the incidence and severity of clinical immunogenicity events. This Review focuses on identifying key unsolved anti-drug antibody-related challenges and offers some pragmatic approaches towards addressing them. Examples are drawn mainly from antibodies, given that the majority of available clinical data are from this class of protein therapeutics. Plausible and seemingly tractable solutions are in sight for some immunogenicity problems, whereas other challenges will likely require completely new approaches.
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Affiliation(s)
- Paul J Carter
- Department of Antibody Engineering, Genentech, Inc., South San Francisco, CA, USA.
| | - Valerie Quarmby
- Department of BioAnalytical Sciences, Genentech, Inc., South San Francisco, CA, USA.
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Leisegang R, Silber Baumann HE, Lennon-Chrimes S, Ito H, Miya K, Genin JC, Plan EL. Immunogenicity dynamics and covariate effects after satralizumab administration predicted with a hidden Markov model. CPT Pharmacometrics Syst Pharmacol 2024; 13:2171-2184. [PMID: 39380259 DOI: 10.1002/psp4.13230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 10/10/2024] Open
Abstract
Immunogenicity is the propensity of a therapeutic protein to generate an immune response to itself. While reporting of antidrug antibodies (ADAs) is increasing, model-based analysis of such data is seldom performed. Model-based characterization of factors affecting the emergence and dissipation of ADAs may inform drug development and/or improve understanding in clinical practice. This analysis aimed to predict ADA dynamics, including the potential influence of individual covariates, following subcutaneous satralizumab administration. Satralizumab is a humanized IgG2 monoclonal recycling IL-6 receptor antagonist antibody approved for treating neuromyelitis optica spectrum disorder (NMOSD). Longitudinal pharmacokinetic (PK) and ADA data from 154 NMOSD patients in two pivotal Phase 3 studies (NCT02028884, NCT02073279) and PK data from one Phase 1 study (SA-001JP) in 72 healthy volunteers were available for this analysis. An existing population PK model was adapted to derive steady-state concentration without ADA for each patient. A mixed hidden Markov model (mHMM) was developed whereby three different states were identified: one absorbing Markov state for non-ADA developer, and two dynamic and inter-connected Markov states-transient ADA negative and positive. Satralizumab exposure and body mass index impacted transition probabilities and, therefore, the likelihood of developing ADAs. In conclusion, the mHMM model was able to describe the time course of ADA development and identify patterns of ADA development in NMOSD patients following treatment with satralizumab, which may allow for the formulation of strategies to reduce the emergence or limit the impact of ADA in the clinical setting.
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Affiliation(s)
- Rory Leisegang
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
| | - Hanna E Silber Baumann
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | | | | | | | - Jean-Christophe Genin
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Elodie L Plan
- Department of Pharmacy, Uppsala University, Uppsala, Sweden
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Lee KR, Gulnaz A, Chae YJ. Drug Interaction-Informed Approaches to Inflammatory Bowel Disease Management. Pharmaceutics 2024; 16:1431. [PMID: 39598554 PMCID: PMC11597736 DOI: 10.3390/pharmaceutics16111431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/01/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a complex and chronic condition that requires the use of various pharmacological agents for its management. Despite advancements in IBD research, the multifaceted mechanisms involved continue to pose significant challenges for strategic prevention. Therefore, it is crucial to prioritize safe and effective treatment strategies using the currently available pharmacological agents. Given that patients with IBD often require multiple medications due to combination therapy or other underlying conditions, a comprehensive understanding of drug interactions is essential for optimizing treatment regimens. In this review, we examined the pharmacological treatment options recommended in the current IBD management guidelines and provided a comprehensive analysis of the known pharmacokinetic interactions associated with these medications. In particular, this review includes recent research results for the impact of anti-drug antibodies (ADAs) on the concentrations of biological agents used in IBD treatment. By leveraging detailed interaction data and employing personalized dosing strategies, healthcare providers can improve therapeutic outcomes and minimize adverse effects, ultimately improving the quality of care for patients with IBD.
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Affiliation(s)
- Kyeong-Ryoon Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Republic of Korea
- Department of Bioscience, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Aneela Gulnaz
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Yoon-Jee Chae
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
- Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju 55338, Republic of Korea
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12
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Pachón-Suárez DI, Zárate-Pinzón L, Cifuentes-González C, Rojas-Carabali W, Mejía-Salgado G, Pineda JS, Peña-Pulgar LF, de-la-Torre A. Immunogenicity of Adalimumab in Patients with Non-Infectious Uveitis: Systematic Review and Meta-Analysis. Ocul Immunol Inflamm 2024; 32:1539-1548. [PMID: 37796609 DOI: 10.1080/09273948.2023.2256850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 10/07/2023]
Abstract
OBJECTIVE To review the prevalence, incidence, and risk factors for developing anti-drug antibodies (AAA) in patients with non-infectious uveitis (NIU) treated with Adalimumab (ADA). METHODS A systematic literature search was performed on PubMed, EMBASE, Virtual Health Library, Cochrane, and medRxiv. Meta-analysis was performed using random effects. RESULTS Nine out of 2,373 studies were included. The prevalence of AAA in NIU patients treated with ADA was 9% (95% CI: 2% to 37%, I2 = 95% with a P<0.01), it was significantly higher in real-life scenarios (observational studies) than in clinical trials. The pooled incidence at 12 months was 27% (CI 95% 16%-42% I2 = 0%). Several factors have been associated with AAA generation in NIU patients, including the non-use of concomitant immunosuppressants, presence of autoimmune systemic disease, female gender, etc. CONCLUSION This study showed that AAA prevalence is higher in real-life scenarios compared to clinical trials. Further research is needed to elucidate the factors that trigger AAA generation in NIU patients.
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Affiliation(s)
- Diana Isabel Pachón-Suárez
- Doctorado en Investigación Clínica, Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
| | - Laura Zárate-Pinzón
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
| | - Carlos Cifuentes-González
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
| | - William Rojas-Carabali
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
| | - Germán Mejía-Salgado
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
- Ophthalmology Interest Group-Universidad del Rosario. (OIG UR). Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | - Juan Sebastián Pineda
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
- Ophthalmology Interest Group-Universidad del Rosario. (OIG UR). Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | - Luisa Fernanda Peña-Pulgar
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
- Ophthalmology Interest Group-Universidad del Rosario. (OIG UR). Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | - Alejandra de-la-Torre
- Neuroscience (NEUROS) Research Group, Neurovitae Research Center, Institute of Translational, Medicine (IMT), Universidad Del Rosario Escuela de Medicina y Ciencias de la Salud, Bogotá, Colombia
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13
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Jani D, Gunsior M, Marsden R, Cowan KJ, Irvin SC, Hay LS, Ward B, Armstrong L, Azadeh M, Cao L, Carmean R, DelCarpini J, Dholakiya SL, Hays A, Hosback S, Hu Z, Kulagina N, Kumar S, Lai CH, Lichtfuss M, Liu HY, Liu S, Mozaffari R, Pan L, Pennucci J, Poupart ME, Saini G, Snoeck V, Storey K, Turner A, Vainshtein I, Verthelyi D, Wala I, Yang L, Yang L. Neutralizing Antibody Sample Testing and Report Harmonization. AAPS J 2024; 26:80. [PMID: 38992280 DOI: 10.1208/s12248-024-00955-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 06/27/2024] [Indexed: 07/13/2024] Open
Abstract
Immunogenicity testing and characterization is an important part of understanding the immune response to administration of a protein therapeutic. Neutralizing antibody (NAb) assays are used to characterize a positive anti-drug antibody (ADA) response. Harmonization of reporting of NAb assay performance and results enables efficient communication and expedient review by industry and health authorities. Herein, a cross-industry group of NAb assay experts have harmonized NAb assay reporting recommendations and provided a bioanalytical report (BAR) submission editable template developed to facilitate agency filings. This document addresses key bioanalytical reporting gaps and provides a report structure for documenting clinical NAb assay performance and results. This publication focuses on the content and presentation of the NAb sample analysis report including essential elements such as the method, critical reagents and equipment, data analysis, study samples, and results. The interpretation of immunogenicity data, including the evaluation of the impact of NAb on safety, exposure, and efficacy, is out of scope of this publication.
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Affiliation(s)
- Darshana Jani
- Bioanalytical and Molecular Assays, Moderna, 325 Binney Street, Cambridge, Massachusetts, USA.
| | - Michele Gunsior
- Translational Sciences, Astria Therapeutics, Boston, Massachusetts, USA
| | | | - Kyra J Cowan
- Drug Metabolism & Pharmacokinetics, New Biological Entities, Merck KGaA, Darmstadt, Germany
| | - Susan C Irvin
- Bioanalytical Sciences, Regeneron Pharmaceuticals, Tarrytown, New York, USA
| | - Laura Schild Hay
- Bioanalytical Lab, PPD Clinical Research Business, Thermo Fisher Scientific, Richmond, Virginia, USA
| | - Bethany Ward
- Bioanalytical Lab, PPD Clinical Research Business, Thermo Fisher Scientific, Richmond, Virginia, USA
| | - Luke Armstrong
- Bioanalytical Operations, BioAgilytix Labs, Durham, North Carolina, USA
| | - Mitra Azadeh
- Bioanalytical and Biomarker Development, Ultragenyx Pharmaceutical, Inc, Novato, California, USA
| | - Liching Cao
- Biomarker and BioAnalytical Sciences, Sangamo Therapeutics, Brisbane, California, USA
| | - Rebecca Carmean
- Bioanalytical Lab, PPD Clinical Research Business, Thermo Fisher Scientific, Richmond, Virginia, USA
| | | | - Sanjay L Dholakiya
- Non-Clinical Disposition and Bioanalysis, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Amanda Hays
- Scientific Office, BioAgilytix Labs, Durham, North Carolina, USA
| | - Sarah Hosback
- Research and Clinical Bioanalytics, CSL, Melbourne, Australia
| | - Zheng Hu
- Translational Safety & Bioanalytical Science, Amgen Inc, Thousand Oaks, California, USA
| | - Nadia Kulagina
- Pharmaceutical Development Services, Smithers, Gaithersburg, Maryland, USA
| | - Seema Kumar
- DMPK and Bioanalysis, Pioneering Medicines at Flagship Pioneering, Cambridge, Massachusetts, USA
| | - Ching Ha Lai
- Bioanalytical Sciences, Regeneron Pharmaceuticals, Tarrytown, New York, USA
| | - Marit Lichtfuss
- Research and Clinical Bioanalytics, CSL, Melbourne, Australia
| | - Hsing-Yin Liu
- Janssen Research & Development LLC, Spring House, Montgomery County, Pennsylvania, USA
| | - Susana Liu
- Clinical Pharmacology, Biologics & Immunogenicity Clinical Assay Group, Pfizer Inc, Kirkland, Quebec, Canada
| | - Reza Mozaffari
- Bioanalysis, Immunogenicity & Biomarkers (BIB), IVIVT, Research, GSK, Collegeville, Pennsylvania, USA
| | - Luying Pan
- Takeda Development Center Americas Inc, Cambridge, Massachusetts, USA
| | - Jason Pennucci
- Bioanalytical Sciences, Moderna, Cambridge, Massachusetts, USA
| | | | - Gurleen Saini
- Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA
| | - Veerle Snoeck
- Translational Biomarkers and Bioanalysis, UCB Biopharma SRL, 1420, Braine-L'Alleud, Belgium
| | - Kristine Storey
- Prometheus Biosciences, Inc., a subsidiary of Merck & Co., Inc, Rahway, New Jersey, USA
| | - Amy Turner
- Pharmaceutical Development Services, Smithers, Gaithersburg, Maryland, USA
| | - Inna Vainshtein
- Discovery and Translational Research, Exelixis, Alameda, California, USA
| | - Daniela Verthelyi
- Office of Pharmaceutical Quality Research, Division IV, Center for Drugs Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Iwona Wala
- Translational Safety and Bioanalytical Sciences, Amgen, Thousand Oaks, California, USA
| | - Lili Yang
- Takeda Development Center Americas, Inc, Cambridge, Massachusetts, USA
| | - Lin Yang
- Bioanalytical Sciences, REGENXBIO Inc, Rockville, Maryland, USA
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14
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Rowe BA, Medina-Carle K, Chen K, Reese KJ, McCarthy KM, Concannon AA, Gunn GR, Gehman AP, Jiang Y, Meyer E. Unique challenges required reassessment and alterations to critical reagents to rescue a neutralizing antibody assay. Bioanalysis 2024; 16:735-745. [PMID: 38884331 PMCID: PMC11389750 DOI: 10.1080/17576180.2024.2360363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 05/23/2024] [Indexed: 06/18/2024] Open
Abstract
Aim: To redevelop a neutralizing antibody (NAb) assay to be much more drug tolerant, have a large dynamic range and have high inhibition when using high levels of positive control (PC).Materials & methods: Early assay data suggested that typical biotin labeling of the capture reagent (Drug 1, produced in a human cell line) was blocking it from binding with the PC or the detection target, and that the detection target was out competing the PC. Methodical biotin labeling experiments were performed at several challenge ratios and an Fc linker was added to the detection target.Results & conclusion: A larger dynamic range, high inhibition and higher drug tolerance were achieved by adding an acid dissociation step to the assay, performing atypical biotin labeling of Drug 1 and switching to a detection target that contained an Fc linker to increase steric hinderance and decrease its binding affinity to Drug 1.
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Affiliation(s)
- Blake A Rowe
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Katie Medina-Carle
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Keguan Chen
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Kimberly J Reese
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Kenneth M McCarthy
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Amy A Concannon
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - George R Gunn
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Andrew P Gehman
- GSK Research Statistics, Biostatistics, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
| | - Yong Jiang
- Janssen Research & Development, 1400 McKean Rd, Lower Gwynedd Township, PA 19002,USA
| | - Erik Meyer
- GSK Precision Medicine, Biomarker & Bioanalytical Platforms, 1250 S Collegeville Rd, Collegeville, PA 19426, USA
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15
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Mohan A, Qiu AY, Lugogo N. Long-term safety, durability of response, cessation and switching of biologics. Curr Opin Pulm Med 2024; 30:303-312. [PMID: 38426355 DOI: 10.1097/mcp.0000000000001067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
PURPOSE OF REVIEW Severe asthma patients suffer from decreased quality of life, and increased asthma symptoms, exacerbations, hospitalizations, and risk of death. Biologics have revolutionized treatment for severe asthma. However, with multiple biologic agents now available, clinicians must consider initial selection the long-term effectiveness of biologics. Additionally, patients have overlapping eligibilities and clinicians may consider switching between biologics for improved response. Finally, careful assessment of biologics cessation is needed for severe asthma patients who depend on these add-on therapies for asthma control. RECENT FINDINGS Evidence for long-term durability and safety varies by biologic agent. In general, initial benefits noted from these agents (ex. exacerbation reduction) is, at minimum, sustained with long term use. Rates of adverse events and serious adverse events, including those requiring cessation of a biologics are low with long term use. Further studies are needed to understand the development of antidrug antibodies but currently their prevalence rates are low. Adverse events and insufficient efficacy are common reasons for biologic cessation or switching. Discontinuation maybe associated with waning of benefits but can be considered in certain situations. Biologic switching can be associated with improved asthma control. SUMMARY Biologics are safe and effective long-term therapies for the management of asthma. Discontinuation must be carefully considered and if possible avoided. Reasons for insufficient efficacy must be evaluated and if needed, biologic switching should be considered.
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Affiliation(s)
- Arjun Mohan
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Anna Y Qiu
- Division of Pulmonary, and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Njira Lugogo
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
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16
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Weiner JA, Natarajan H, McIntosh CJ, Yang ES, Choe M, Papia CL, Axelrod KS, Kovacikova G, Pegu A, Ackerman ME. Selection of positive controls and their impact on anti-drug antibody assay performance. J Immunol Methods 2024; 528:113657. [PMID: 38479453 DOI: 10.1016/j.jim.2024.113657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 03/03/2024] [Indexed: 03/17/2024]
Abstract
Development of assays to reliably identify and characterize anti-drug antibodies (ADAs) depends on positive control anti-idiotype (anti-id) reagents, which are used to demonstrate that the standards recommended by regulatory authorities are met. This work employs a set of therapeutic antibodies under clinical development and their corresponding anti-ids to investigate how different positive control reagent properties impact ADA assay development. Positive controls exhibited different response profiles and apparent assay analytical sensitivity values depending on assay format. Neither anti-id affinity for drug, nor sensitivity in direct immunoassays related to sensitivity in ADA assays. Anti-ids were differentially able to detect damage to drug conjugates used in bridging assays and were differentially drug tolerant. These parameters also failed to relate to assay sensitivity, further complicating selection of anti-ids for use in ADA assay development based on functional characteristics. Given this variability among anti-ids, alternative controls that could be employed across multiple antibody drugs were investigated as a more uniform means to define ADA detection sensitivity across drug products and assay protocols, which could help better relate assay results to clinical risks of ADA responses. Overall, this study highlights the importance of positive control selection to reliable detection and clinical interpretation of the presence and magnitude of ADA responses.
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Affiliation(s)
- Joshua A Weiner
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA
| | - Harini Natarajan
- Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, NH, USA
| | - Calum J McIntosh
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA
| | - Eun Sung Yang
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Misook Choe
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cassidy L Papia
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA
| | | | | | - Amarendra Pegu
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Margaret E Ackerman
- Thayer School of Engineering, Dartmouth College, Hanover, NH, USA; Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, NH, USA.
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17
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Delgado SR, Faissner S, Linker RA, Rammohan K. Key characteristics of anti-CD20 monoclonal antibodies and clinical implications for multiple sclerosis treatment. J Neurol 2024; 271:1515-1535. [PMID: 37906325 PMCID: PMC10973056 DOI: 10.1007/s00415-023-12007-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 11/02/2023]
Abstract
The recent success of anti-CD20 monoclonal antibody therapies in the treatment of multiple sclerosis (MS) has highlighted the role of B cells in the pathogenesis of MS. In people with MS, the inflammatory characteristics of B-cell activity are elevated, leading to increased pro-inflammatory cytokine release, diminished anti-inflammatory cytokine production and an accumulation of pathogenic B cells in the cerebrospinal fluid. Rituximab, ocrelizumab, ofatumumab, ublituximab and BCD-132 are anti-CD20 therapies that are either undergoing clinical development, or have been approved, for the treatment of MS. Despite CD20 being a common target for these therapies, differences have been reported in their mechanistic, pharmacological and clinical characteristics, which may have substantial clinical implications. This narrative review explores key characteristics of these therapies. By using clinical trial data and real-world evidence, we discuss their mechanisms of action, routes of administration, efficacy (in relation to B-cell kinetics), safety, tolerability and convenience of use. Clinicians, alongside patients and their families, should consider the aspects discussed in this review as part of shared decision-making discussions to improve outcomes and health-related quality of life for people living with MS.
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Affiliation(s)
- Silvia R Delgado
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Simon Faissner
- Department of Neurology, Ruhr-University Bochum, St Josef-Hospital, Bochum, Germany
| | - Ralf A Linker
- Department of Neurology, University Hospital Regensburg, Regensburg, Germany
| | - Kottil Rammohan
- Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA.
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18
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Spreafico A, Couselo EM, Irmisch A, Bessa J, Au-Yeung G, Bechter O, Svane IM, Sanmamed MF, Gambardella V, McKean M, Callahan M, Dummer R, Klein C, Umaña P, Justies N, Heil F, Fahrni L, Opolka-Hoffmann E, Waldhauer I, Bleul C, Staack RF, Karanikas V, Fowler S. Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure. Front Oncol 2024; 14:1346502. [PMID: 38577337 PMCID: PMC10991832 DOI: 10.3389/fonc.2024.1346502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
Introduction Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1-2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.
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Affiliation(s)
- Anna Spreafico
- Department of Medicine, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada
| | - Eva Muñoz Couselo
- Department of Medical Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Anja Irmisch
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Juliana Bessa
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - George Au-Yeung
- Department of Medical Oncology, Peter MacCallum Cancer Center and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
| | - Oliver Bechter
- Department of General Medical Oncology, Universitair Ziekenhuis (UZ), Leuven, Leuven, Belgium
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy and Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Miguel F. Sanmamed
- Department of Medical Oncology, Clínica Universidad de Navarra and Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), Pamplona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
| | - Valentina Gambardella
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Meredith McKean
- Sarah Cannon Research Institute at Tennessee Oncology, Nashville, TN, United States
| | - Margaret Callahan
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, United States
| | - Reinhard Dummer
- Department of Dermatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Christian Klein
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Pablo Umaña
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Nicole Justies
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Florian Heil
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Linda Fahrni
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Eugenia Opolka-Hoffmann
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Inja Waldhauer
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Conrad Bleul
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Roland F. Staack
- Roche Pharma Research & Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Vaios Karanikas
- Roche Pharma Research & Early Development, Roche Innovation Center Zurich, Zurich, Switzerland
| | - Stephen Fowler
- Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
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19
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Williams JH, Liao KH, Yin D, Meng X. Implications of Immunogenicity Testing for Therapeutic Monoclonal Antibodies: A Quantitative Pharmacology Framework. AAPS J 2024; 26:31. [PMID: 38453809 DOI: 10.1208/s12248-024-00901-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/17/2024] [Indexed: 03/09/2024] Open
Abstract
The interpretation of immunogenicity results for a mAb product and prediction of its clinical consequences remain difficult, despite enormous advances in methodologies and efforts toward the best practice for consistent data generation and reporting. To this end, the contribution from the clinical pharmacology discipline has been largely limited to comparing descriptively the pharmacokinetic (PK) profiles by antidrug antibodies (ADA) status or testing the significance of ADA as a covariate in a population PK setting, similar to the practice for small-molecule drugs in investigating the effect of an intrinsic/extrinsic factor on the drug disposition. There is a need for a mAb disposition framework that captures the dynamics of ADA formation and drug's interactions with the ADA and target as parts of the drug distribution and elimination. Here we describe such a framework and examine it against the PK, ADA, and clinical response data from a phase 3 trial in patients treated with adalimumab. The proposed framework offered a generalized understanding of how the dose, target affinity, and drug/ADA analyte forms affects the manifestation of ADA response with regard to its detections and alterations of drug disposition and effectiveness. Furthermore, as an example, its utility for dose considerations was demonstrated through predicting for late-stage trials of a PCSK9 inhibitor in terms of development in ADA incidence and titers, and consequences on the drug disposition, interaction with target, and downstream lowering effect on LDL-C.
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Affiliation(s)
| | - Kai H Liao
- Pfizer Inc, San Diego, CA, USA
- Arcus Biosciences, Hayward, CA, USA
| | | | - Xu Meng
- Pfizer Inc, San Diego, CA, USA
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20
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Brekkan A, Lledo-Garcia R, Lacroix B, Jönsson S, Karlsson MO, Plan EL. Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach. J Pharmacokinet Pharmacodyn 2024; 51:65-75. [PMID: 37943398 PMCID: PMC10884144 DOI: 10.1007/s10928-023-09890-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 10/01/2023] [Indexed: 11/10/2023]
Abstract
Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.
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Affiliation(s)
- Ari Brekkan
- Department of Pharmacy, Uppsala University, Box 580, Uppsala, SE-75123, Sweden
| | | | | | - Siv Jönsson
- Department of Pharmacy, Uppsala University, Box 580, Uppsala, SE-75123, Sweden
| | - Mats O Karlsson
- Department of Pharmacy, Uppsala University, Box 580, Uppsala, SE-75123, Sweden
| | - Elodie L Plan
- Department of Pharmacy, Uppsala University, Box 580, Uppsala, SE-75123, Sweden.
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21
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Galle P, Finn RS, Mitchell CR, Ndirangu K, Ramji Z, Redhead GS, Pinato DJ. Treatment-emergent antidrug antibodies related to PD-1, PD-L1, or CTLA-4 inhibitors across tumor types: a systematic review. J Immunother Cancer 2024; 12:e008266. [PMID: 38238030 PMCID: PMC10806538 DOI: 10.1136/jitc-2023-008266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Increased understanding of how the immune system regulates tumor growth has innovated the use of immunotherapeutics to treat various cancers. The impact of such therapies, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, on the production of antidrug antibodies (ADAs) and their impact on outcomes, is poorly understood. This study aims to evaluate the clinical trial evidence on ADA incidence associated with PD-1, PD-L1, and CTLA-4 inhibitors in the treatment of cancer and to assess associations between treatment administered, ADA incidence, and treatment outcomes. METHODS Embase®, Medline®, and EBM Reviews were searched via the OVID® platform on February 15, 2022. Conference proceedings, clinical trial registries, and global regulatory and reimbursement body websites were also searched. Eligible publications included clinical trials enrolling patients receiving cancer treatment with either PD-1, PD-L1, or CTLA-4 reporting outcomes including incidence or prevalence of ADAs and the impact of immunogenicity on treatment safety and efficacy. Reference lists of eligible publications were also searched. The review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and evidence quality assessment was conducted using the appropriate Joanna Briggs Institute Critical Appraisal tool. RESULTS After screening 4160 records and reviewing 97 full publications, a total of 34 publications reporting on 68 trials were included. A further 41 relevant clinical trials were identified on ClinicalTrials.gov and a further 32 from searches of packaging inserts. In total, 141 relevant trials covering 15 different checkpoint inhibitors and 16 different tumor types were included. Across the included trials, atezolizumab was associated with the highest incidence of ADAs (29.6% of 639 patients), followed by nivolumab (11.2% of 2,085 patients). Combination checkpoint inhibitor treatment appeared to increase the rate of ADAs versus monotherapy. Only 17 trials reported on the impact of ADAs on treatment outcomes with mixed results for the impact of ADAs on treatment efficacy, safety, and pharmacokinetics. CONCLUSIONS Checkpoint inhibitors for the treatment of cancer are immunogenic, with the incidence of treatment-emergent ADAs varying between individual therapies. It remains unclear what impact ADAs have on treatment outcomes.
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Affiliation(s)
- Peter Galle
- University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Richard S Finn
- University of California Los Angeles, Los Angeles, California, USA
| | | | | | | | | | - David J Pinato
- Surgery and Cancer, Imperial College London, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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22
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Peek VL, Lemen DM, Konrad RJ, Wen Y. A competitive ligand binding assay for detection of neutralizing antibodies against an insulin analog. J Immunol Methods 2023; 523:113575. [PMID: 37844794 DOI: 10.1016/j.jim.2023.113575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/15/2023] [Accepted: 10/13/2023] [Indexed: 10/18/2023]
Abstract
Biotherapeutics have the potential to trigger undesired immune responses in the patients. For therapeutic proteins, immunogenicity is manifested as anti-drug antibodies (ADA). Because ADA could compromise pharmacokinetics, efficacy, and safety, regulatory agencies require immunogenicity assessment during clinical development. A tiered bioanalytical approach is recommended to monitor clinical immunogenicity, and neutralizing antibodies (NAb) are studied in Tier 4 if the molecule is immunogenic. Although cell-based assays, which reflect the pharmacological mechanism of action, are in some cases the preferred assay format for detecting NAbs, they are associated with operational complexity and sometimes suboptimal assay performance. Alternatively, non-cell-based assays have also been developed and implemented. In our current study, a competitive ligand binding assay (CLBA) was developed to detect NAbs for insulin efsitora alfa (efsitora, basal insulin Fc, LY3209590), a novel fusion protein being studied for the treatment of Type 1 diabetes and Type 2 diabetes. The CLBA demonstrated acceptable sensitivity, drug tolerance, precision, and robustness, and thus provides a suitable approach for detecting NAbs against efsitora.
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Affiliation(s)
- Victoria L Peek
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Deven M Lemen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
| | - Yi Wen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
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23
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Tudan C. Good clinical practices in the bioanalytical laboratory. Bioanalysis 2023; 15:1381-1388. [PMID: 37737137 DOI: 10.4155/bio-2023-0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/23/2023] Open
Abstract
Despite the existence of good clinical practice guidelines, the way in which they are applied to the bioanalytical laboratory remains unclear. Aspects of patient confidentiality, informed consent and subject withdrawal; addressing unblinding associated with sample analysis, including repeat analysis and incurred sample reanalysis; or the differences in responsibilities between the sponsor and contract research organization are not articulated by the US FDA within the bioanalytical setting, and for most bioanalytical laboratories this remains a gap in their standard operating procedures. The aim of this article is to identify and clarify the aspects of the good clinical practices that are applicable to the bioanalytical laboratory when conducting bioanalysis with clinical samples, and to address potential gaps in the bioanalytical laboratory when it comes to clinical sample bioanalysis.
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24
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Yang X, Siradze K, Sperinde G, Arjomandi A, Fischer S. Evaluation of multiple immunoassay formats for detection of anti-drug antibodies to zinpentraxin alfa. J Immunol Methods 2023; 522:113573. [PMID: 37816404 DOI: 10.1016/j.jim.2023.113573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/31/2023] [Accepted: 10/06/2023] [Indexed: 10/12/2023]
Abstract
Zinpentraxin alfa (rhPTX-2; PRM-151) is currently being developed for the treatment of fibrotic diseases such as idiopathic pulmonary fibrosis and myelofibrosis. Notably, because it is administered chronically and has an endogenously expressed counterpart, clinical studies of zinpentraxin alpha must include immunogenicity assessments. Since the typical homogenous bridging ELISA assay does not adequately measure anti-drug antibodies (ADAs) against zinpentraxin alfa, additional assay formats have been developed to evaluate immunogenicity of this therapeutic. Here, we present the evaluation of four distinct assay formats that were used to measure zinpentraxin alpha ADA: step-wise bridging, direct binding, total ADA, and the semi-homogeneous formats, based on multiple parameters including assay sensitivity, precision, and drug tolerance. This paper presents the full details of method development for each of the aforementioned assay formats including evaluation of sample pre-treatment, determination of cut point, and assessment of assay performance by analyzing a subset of clinical samples. Overall, the semi-homogenous ADA assay format with no sample pre-treatment was selected for the measurement of zinpentraxin alpha immunogenicity as it provided the desired sensitivity, drug tolerance, and reproducibility. Our study emphasizes the importance of assay format evaluation during drug development and the necessity to select the most suitable assay format and sample pre-treatment method by which to evaluate therapeutic drug immunogenicity.
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Affiliation(s)
- Xiaoyun Yang
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
| | - Ketevan Siradze
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Gizette Sperinde
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Audrey Arjomandi
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
| | - Saloumeh Fischer
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA
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25
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Butala-Flores E, Nguyen T, Selvan N, Armstrong L, Miller M, Kamen L, Lester T, Wernyj R, Khanna R, McNally J, Hays A. Validation of Anti-Adeno Associated Virus Serotype rh10 (AAVrh.10) Total and Neutralizing Antibody Immunogenicity Assays. Pharm Res 2023; 40:2383-2397. [PMID: 37880551 PMCID: PMC10661749 DOI: 10.1007/s11095-023-03625-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 10/12/2023] [Indexed: 10/27/2023]
Abstract
Immunogenicity assessment of Adeno-Associated Virus (AAV) vectors is a critical part of gene therapy drug development. Whether the assays are used for inclusion/exclusion criteria or to monitor the safety and efficacy of the gene therapy, they are critical bioanalytical assessments. While total anti-AAV assays are perceived as easier to develop and implement than neutralizing anti-AAV assays, the gene therapy field is still nascent, and it is not yet clear which of the assays should be implemented at what stage of drug development. Recently AAVrh.10 has gained interest for use in gene therapies targeting cardiac, neurological, and other diseases due to its enhanced transduction efficiency. There is limited information on anti-AAVrh.10 antibodies and their clinical impact; thus, the information presented herein documents the validation of both a total antibody assay (TAb) and a neutralizing antibody (NAb) assay for anti-AAVrh.10 antibodies. In this manuscript, the validation was performed in accordance with the 2019 FDA immunogenicity guidance with additional evaluations to comply with CLIA where applicable. The AAVrh.10 TAb and NAb assays were compared in terms of sensitivity, drug tolerance, and precision, along with a concordance analysis using the same individual serum samples. This comparison gave insight into the utility of each format as a screening assay for inclusion into clinical studies.
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26
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Hartman K, Steiner G, Siegel M, Looney CM, Hickling TP, Bray-French K, Springer S, Marban-Doran C, Ducret A. Expanding the MAPPs Assay to Accommodate MHC-II Pan Receptors for Improved Predictability of Potential T Cell Epitopes. BIOLOGY 2023; 12:1265. [PMID: 37759665 PMCID: PMC10525474 DOI: 10.3390/biology12091265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023]
Abstract
A critical step in the immunogenicity cascade is attributed to human leukocyte antigen (HLA) II presentation triggering T cell immune responses. The liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based major histocompatibility complex (MHC) II-associated peptide proteomics (MAPPs) assay is implemented during preclinical risk assessments to identify biotherapeutic-derived T cell epitopes. Although studies indicate that HLA-DP and HLA-DQ alleles are linked to immunogenicity, most MAPPs studies are restricted to using HLA-DR as the dominant HLA II genotype due to the lack of well-characterized immunoprecipitating antibodies. Here, we address this issue by testing various commercially available clones of MHC-II pan (CR3/43, WR18, and Tü39), HLA-DP (B7/21), and HLA-DQ (SPV-L3 and 1a3) antibodies in the MAPPs assay, and characterizing identified peptides according to binding specificity. Our results reveal that HLA II receptor-precipitating reagents with similar reported specificities differ based on clonality and that MHC-II pan antibodies do not entirely exhibit pan-specific tendencies. Since no individual antibody clone is able to recover the complete HLA II peptide repertoire, we recommend a mixed strategy of clones L243, WR18, and SPV-L3 in a single immunoprecipitation step for more robust compound-specific peptide detection. Ultimately, our optimized MAPPs strategy improves the predictability and additional identification of T cell epitopes in immunogenicity risk assessments.
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Affiliation(s)
- Katharina Hartman
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Guido Steiner
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Michel Siegel
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Cary M. Looney
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Timothy P. Hickling
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Katharine Bray-French
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Sebastian Springer
- School of Science, Department of Biochemistry and Cell Biology, Constructor University, Campus Ring 1, 28759 Bremen, Germany
| | - Céline Marban-Doran
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
| | - Axel Ducret
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland (C.M.L.)
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27
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Li A, Swanson M, Sullivan N, Homan Y, Nahas D, Mukhopadhyay S, Li HH, Cao Y, Xu W, Tang H, Vora KA, Chen Z. Phage-derived anti-idiotype and anti-YTE antibodies in development of MK-1654 pharmacokinetic and immune response assays. Bioanalysis 2023; 15:1049-1067. [PMID: 37515532 DOI: 10.4155/bio-2023-0081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2023] Open
Abstract
Background: MK-1654 is a fully human monoclonal antibody with YTE mutations currently in phase III clinical trials for prophylactic use in protecting infants from human respiratory syncytial virus infection. Materials & methods: We generated anti-idiotype (anti-ID) and anti-YTE antibodies against MK-1654 by panning with MorphoSys HuCal phage libraries, and used the antibodies in the development of MK-1654 pharmacokinetic (PK) and immune response (IR) assays. Results: Detection of MK-1654 in nonhuman primate and human nasal wash samples showed combined use of anti-ID and anti-YTE antibodies can deliver desired sensitivity and accuracy in PK studies. IR studies showed anti-ID can serve as suitable positive control in neutralizing antibody assays. Conclusion: Phage-derived anti-IDs and anti-YTEs are suitable for PK and IR assays.
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Affiliation(s)
- April Li
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
| | - Michael Swanson
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
- Current address: Janssen Pharmaceutical, Ambler, PA 19002, USA
| | - Nicole Sullivan
- Infectious Diseases and Vaccine Research, Merck and Co., Inc., West Point, PA 19486, USA
| | - Ying Homan
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
| | - Debbie Nahas
- Infectious Diseases and Vaccine Research, Merck and Co., Inc., West Point, PA 19486, USA
| | - Shreya Mukhopadhyay
- Infectious Diseases and Vaccine Research, Merck and Co., Inc., West Point, PA 19486, USA
| | - Hualin Helen Li
- Analytical Research and Development, Merck and Co., Inc., West Point, PA 19486, USA
| | - Yu Cao
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
| | - Weifeng Xu
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
| | - Huaping Tang
- PCD Regulated Immunogenicity and Molecular, Merck and Co., Inc., West Point, PA 19486, USA
- Current address: GSK Pharmaceutical, Collegeville, PA 19426, USA
| | - Kalpit A Vora
- Infectious Diseases and Vaccine Research, Merck and Co., Inc., West Point, PA 19486, USA
| | - Zhifeng Chen
- Infectious Diseases and Vaccine Research, Merck and Co., Inc., West Point, PA 19486, USA
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28
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Yin Z, Guerrero J, Melendez R, Andrews B, Peng K. Development of a Cell-based Neutralizing Antibody Assay for Zinpentraxin Alfa: Challenges and Mitigation Strategies. AAPS J 2023; 25:75. [PMID: 37468730 DOI: 10.1208/s12248-023-00841-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/01/2023] [Indexed: 07/21/2023] Open
Abstract
Therapeutic protein drugs can potentially induce immune responses in patients and result in the production of anti-drug antibodies (ADAs), including a subset of ADAs called neutralizing antibodies (NAbs) that might cause loss of efficacy by inhibiting clinical activities of the drug. Herein, we describe the unique challenges encountered during the development of a fit-for-purpose cell-based NAb assay for a new protein modality, zinpentraxin alfa, including our strategies for assay design to overcome various matrix interferences and improve assay drug tolerance. We demonstrated that a typical biotin-drug extraction with acid dissociation (BEAD) approach alone was not sufficient to eliminate matrix interferences in this assay. Instead, the combination of the BEAD and ZebaTM spin size exclusion plate (SEP) was required to achieve the desirable assay performance. We also demonstrated that appropriate acidic buffers were critical in sample pretreatment to improve assay drug tolerance, which not only dissociated the drug/NAb immune complex but also effectively and irreversibly denatured the free drug. The final assay performed well with confirmed assay robustness and suitability for the clinical applications.
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Affiliation(s)
- Zhaojun Yin
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
| | - Joyce Guerrero
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Rachel Melendez
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Ben Andrews
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Kun Peng
- BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
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29
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Chen SF, Yeh FC, Chen CY, Chang HY. Tailored therapeutic decision of rheumatoid arthritis using proteomic strategies: how to start and when to stop? Clin Proteomics 2023; 20:22. [PMID: 37301840 DOI: 10.1186/s12014-023-09411-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Unpredictable treatment responses have been an obstacle for the successful management of rheumatoid arthritis. Although numerous serum proteins have been proposed, there is a lack of integrative survey to compare their relevance in predicting treatment outcomes in rheumatoid arthritis. Also, little is known about their applications in various treatment stages, such as dose modification, drug switching or withdrawal. Here we present an in-depth exploration of the potential usefulness of serum proteins in clinical decision-making and unveil the spectrum of immunopathology underlying responders to different drugs. Patients with robust autoimmunity and inflammation are more responsive to biological treatments and prone to relapse during treatment de-escalation. Moreover, the concentration changes of serum proteins at the beginning of the treatments possibly assist early recognition of treatment responders. With a better understanding of the relationship between the serum proteome and treatment responses, personalized medicine in rheumatoid arthritis will be more achievable in the near future.
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Affiliation(s)
- Shuo-Fu Chen
- Department of Heavy Particles & Radiation Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fu-Chiang Yeh
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ching-Yun Chen
- Department of Biomedical Sciences and Engineering, Institute of Biomedical Engineering and Nanomedicine, National Central University, Taoyuan, Taiwan
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan
| | - Hui-Yin Chang
- Department of Biomedical Sciences and Engineering, Institute of Systems Biology and Bioinformatics, National Central University, No. 300, Zhongda Rd., Zhongli District, Taoyuan, 320317, Taiwan.
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30
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Chen ML, Nopsopon T, Akenroye A. Incidence of Anti-Drug Antibodies to Monoclonal Antibodies in Asthma: A Systematic Review and Meta-Analysis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1475-1484.e20. [PMID: 36716995 PMCID: PMC10601343 DOI: 10.1016/j.jaip.2022.12.046] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/23/2022] [Accepted: 12/30/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND Antidrug antibodies (ADAs) may worsen the efficacy and safety of biologics. However, little is known about the incidence of ADAs associated with the 6 biologics approved for the treatment of asthma in the United States. OBJECTIVE To elucidate the incidence of ADAs and their impact on reported clinical outcomes. METHODS Systematic review and meta-analyses of randomized controlled trials, open-label extension studies, and nonrandomized studies of biologics in patients with asthma indexed in PubMed, Embase, and CENTRAL between January 1, 2000, and July 9, 2022, were carried out. The primary outcomes were treatment-emergent ADAs (incidence) and ADA prevalence. RESULTS A total of 46 studies met the eligibility criteria. ADA incidence over follow-up was 2.91% (95% CI, 1.60-4.55) and was highest in the benralizumab studies (8.35%), with a risk ratio of 4.9 (2.69-8.92) when compared with placebo, and lowest in the omalizumab studies (0.00%). Incidence was 7.61% in the dupilumab studies, 4.39% in reslizumab, 3.63% in mepolizumab, and 1.12% in the tezepelumab studies. Incidence of neutralizing antibodies was 0.00% to 10.74% and was highest for benralizumab (7.12%). Incidence of neutralizing antibodies was higher in the benralizumab every 8 weeks (8.17%) versus every 4 weeks arms (5.81%). Results were consistent in subgroup analyses by study type and length of follow-up. CONCLUSIONS Approximately 2.9% of individuals in the included studies developed ADAs over study follow-up period. The incidence was highest in the benralizumab group and lowest in the omalizumab group. The subcutaneous route and longer dosing intervals were associated with higher ADA development.
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Affiliation(s)
- Ming-Li Chen
- Harvard T.H. Chan School of Public Health, Boston, Mass; Chung Shan Medical University, Taichung, Taiwan
| | - Tanawin Nopsopon
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Chulalongkorn University, Bangkok, Thailand
| | - Ayobami Akenroye
- Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, Mass; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Mass; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md.
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31
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Dai C, Huang YH, Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int Immunopharmacol 2023; 114:109545. [PMID: 36508920 DOI: 10.1016/j.intimp.2022.109545] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVE Inflammatory Bowel Diseases (IBD) are chronic nonspecific intestinal inflammatory diseases with a relapsing-remitting course, including Ulcerative Colitis (UC) and Crohn's Disease (CD). Combination therapy has been proposed as a strategy to enhance treatment efficacy in IBD. The aim of this study is to summarize current evidence and perspectives on combination therapies in IBD. METHODS Electronic databases such as PubMed, Ovid Embase, Medline, and Cochrane CENTRAL were searched to identify relevant studies. RESULTS Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy in inducing and maintaining remission in IBD. Data on the combination of other biological agents such as adalimumab, vedolizumab, ustekinumab, and immunosuppressors is lacking or showed conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis (ASUC). Dual Targeted Therapy, which is the combination of two biological agents and/or small molecules, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Some safety concerns such as adverse events (serious and opportunistic infections) and malignancies (lymphoma and nonmelanoma skin cancer) were raised in combination therapies. CONCLUSIONS Combination therapies seem to be effective in some IBD patients such as refractory IBD patients or patients with extraintestinal manifestations, but it might be associated with an increased risk of adverse events and malignancies.
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Affiliation(s)
- Cong Dai
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China.
| | - Yu-Hong Huang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China
| | - Min Jiang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China
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32
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Megna BW, Vaughn BP. Therapeutic Drug Monitoring in Practice for Inflammatory Bowel Disease. Curr Gastroenterol Rep 2022; 24:191-200. [PMID: 36459387 DOI: 10.1007/s11894-022-00854-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/11/2022] [Indexed: 06/17/2023]
Abstract
PURPOSE OF REVIEW To outline the development, rationale, and practical use of therapeutic drug monitoring in patients with inflammatory bowel disease. RECENT FINDINGS Therapeutic drug monitoring is traditionally discussed in terms of a proactive or reactive approach. However, these terms are not always consistently defined and can be confusing when translating research to clinical practice. Personalized approaches incorporating clinical context and precision medicine are emerging. Personalized therapeutic drug monitoring combines a structured and proactive strategy for monitoring biologic concentrations as well as identification of antidrug antibody development or subtherapeutic dosing in the setting of loss of response. Optimizing biologic therapy can improve outcomes and avoid loss of response. Why, when, and how we measure drug troughs and anti-drug antibodies is a moving target, though what is known is that the appropriate and evidence-based use of this practice prevents adverse events and improves outcomes in patients with inflammatory bowel disease.
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Affiliation(s)
- Bryant W Megna
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA.
| | - Byron P Vaughn
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, MN, USA
- Inflammatory Bowel Disease Program, University of Minnesota, Minneapolis, MN, USA
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Edelmann MR. Radiolabelling small and biomolecules for tracking and monitoring. RSC Adv 2022; 12:32383-32400. [PMID: 36425706 PMCID: PMC9650631 DOI: 10.1039/d2ra06236d] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/02/2022] [Indexed: 11/13/2022] Open
Abstract
Radiolabelling small molecules with beta-emitters has been intensively explored in the last decades and novel concepts for the introduction of radionuclides continue to be reported regularly. New catalysts that induce carbon/hydrogen activation are able to incorporate isotopes such as deuterium or tritium into small molecules. However, these established labelling approaches have limited applicability for nucleic acid-based drugs, therapeutic antibodies, or peptides, which are typical of the molecules now being investigated as novel therapeutic modalities. These target molecules are usually larger (significantly >1 kDa), mostly multiply charged, and often poorly soluble in organic solvents. However, in preclinical research they often require radiolabelling in order to track and monitor drug candidates in metabolism, biotransformation, or pharmacokinetic studies. Currently, the most established approach to introduce a tritium atom into an oligonucleotide is based on a multistep synthesis, which leads to a low specific activity with a high level of waste and high costs. The most common way of tritiating peptides is using appropriate precursors. The conjugation of a radiolabelled prosthetic compound to a functional group within a protein sequence is a commonly applied way to introduce a radionuclide or a fluorescent tag into large molecules. This review highlights the state-of-the-art in different radiolabelling approaches for oligonucleotides, peptides, and proteins, as well as a critical assessment of the impact of the label on the properties of the modified molecules. Furthermore, applications of radiolabelled antibodies in biodistribution studies of immune complexes and imaging of brain targets are reported.
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Affiliation(s)
- Martin R Edelmann
- Department of Pharmacy and Pharmacology, University of Bath Bath BA2 7AY UK
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Therapeutic Modalities, Small Molecule Research, Isotope Synthesis, F. Hoffmann-La Roche Ltd CH-4070 Basel Switzerland
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Joyce A, Shea C, You Z, Gorovits B, Lepsy C. Determination of Anti-drug Antibody Affinity in Clinical Study Samples Provides a Tool for Evaluation of Immune Response Maturation. AAPS J 2022; 24:114. [PMID: 36324032 PMCID: PMC9629885 DOI: 10.1208/s12248-022-00759-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Characterization of clinical anti-drug antibody (ADA) responses to biotherapeutics can be important to understanding the consequences of immunogenicity. ADA are expected to be polyclonal, with composition and affinities that evolve over time. Measuring ADA binding affinity can be complicated by the polyclonal nature of response, residual drug in sample, and low ADA levels. We developed a novel workflow to determine the apparent ADA affinity (KD) against a monoclonal antibody biotherapeutic, PF-06480605. An affinity capture elution pre-treatment step was used to isolate ADA and remove residual drug interference from samples. Solution-phase equilibrium incubation was performed using drug and sample ADA as variable and fixed binding interactants, respectively. Unbound ADA concentration was measured using a Singulex Erenna ligand-binding assay (LBA) method. Apparent ADA KD values were calculated using a custom R Shiny algorithm. KD values determined for ADA positive samples showed good correlation with other immunogenicity parameters, including titers and neutralizing antibody (NAb) activity with a general increase in affinity over time, indicative of a maturing immune response. Time of onset of high affinity responses (KD < 100 pM) varied between patients, ranging from 16 to 24 weeks. Antibody responses appeared monophasic at earlier time points, trending towards a biphasic response with a variable transition time and general increase in proportion of high affinity ADA over time. Herein, we provide a novel, sensitive bioanalytical method to determine the KD of ADA in clinical samples. The observed decrease in ADA KD is consistent with evidence of a maturing immune response.
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Affiliation(s)
- Alison Joyce
- grid.410513.20000 0000 8800 7493Pfizer, Inc., Worldwide Research & Development, Biomedicine Design, 1 Burtt Road, Andover, Massachusetts USA
| | - Christopher Shea
- grid.410513.20000 0000 8800 7493Pfizer, Inc., Worldwide Research & Development, Biomedicine Design, 1 Burtt Road, Andover, Massachusetts USA
| | - Zhiping You
- grid.410513.20000 0000 8800 7493Pfizer, Inc, Worldwide Research & Development, Early Clinical Development, 1 Burtt Road, Andover, Massachusetts USA
| | - Boris Gorovits
- grid.410513.20000 0000 8800 7493Pfizer, Inc., Worldwide Research & Development, Biomedicine Design, 1 Burtt Road, Andover, Massachusetts USA ,grid.510014.1Present Address: Development Sciences, Sana Biotechnology, Inc., 300 Technology Square, Cambridge, Massachusetts USA
| | - Christopher Lepsy
- grid.410513.20000 0000 8800 7493Pfizer, Inc., Worldwide Research & Development, Biomedicine Design, 1 Burtt Road, Andover, Massachusetts USA
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35
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Petric Z, Goncalves J, Paixao P. Under the Umbrella of Clinical Pharmacology: Inflammatory Bowel Disease, Infliximab and Adalimumab, and a Bridge to an Era of Biosimilars. Pharmaceutics 2022; 14:1766. [PMID: 36145514 PMCID: PMC9505802 DOI: 10.3390/pharmaceutics14091766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/19/2022] [Indexed: 11/16/2022] Open
Abstract
Monoclonal antibodies (MAbs) have revolutionized the treatment of many chronic inflammatory diseases, including inflammatory bowel disease (IBD). IBD is a term that comprises two quite similar, yet distinctive, disorders-Crohn's disease (CD) and ulcerative colitis (UC). Two blockbuster MAbs, infliximab (IFX) and adalimumab (ADL), transformed the pharmacological approach of treating CD and UC. However, due to the complex interplay of pharmacology and immunology, MAbs face challenges related to their immunogenicity, effectiveness, and safety. To ease the burden of IBD and other severe diseases, biosimilars have emerged as a cost-effective alternative to an originator product. According to the current knowledge, biosimilars of IFX and ADL in IBD patients are shown to be as safe and effective as their originators. The future of biosimilars, in general, is promising due to the potential of making the health care system more sustainable. However, their use is accompanied by misconceptions regarding their effectiveness and safety, as well as by controversy regarding their interchangeability. Hence, until a scientific consensus is achieved, scientific data on the long-term effectiveness and safety of biosimilars are needed.
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Affiliation(s)
- Zvonimir Petric
- Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
| | - Joao Goncalves
- Biopharmaceutical and Molecular Biotechnology Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
| | - Paulo Paixao
- Department of Pharmacological Sciences, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, 1649-004 Lisboa, Portugal
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36
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Norden A, Oulee A, Munawar L, Javadi SS, Han G, Wu JJ. Anti-drug antibodies of IL-17 inhibitors for psoriasis: a systematic review. J DERMATOL TREAT 2022; 33:3080-3085. [PMID: 35972196 DOI: 10.1080/09546634.2022.2114288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Biologics may elicit the production of anti-drug antibodies (ADAs), the clinical significance of which is not fully understood. ADA development in psoriasis patients on IL-17 inhibitors was evaluated by incidence, impact on efficacy, and relationship with adverse events. We systematically searched PubMed, Cochrane, and Embase databases, identifying 456 references. 17 studies met inclusion criteria. ADA incidence was: 0% to 5.5% (secukinumab), 11% to 19.4% (ixekizumab), 0% to 3.3% (brodalumab), and 19% to 39% (bimekizumab). Neutralizing antibody incidence was: 0% to 1.5% (secukinumab), 0% to 3.5% (ixekizumab), and 0% (brodalumab). ADA presence alone with secukinumab, ixekizumab, and bimekizumab did not impact drug efficacy. Brodalumab was the only one of the IL-17 inhibitors, which showed a reduction in efficacy in ADA + patients. In one analysis, high ADA titers to ixekizumab were associated with diminished treatment response. ADAs to secukinumab and bimekizumab were not associated with adverse events. There were limited data on ADAs and safety with ixekizumab or brodalumab. Overall, when monitoring patients on secukinumab, ADAs, titers, and the presence of neutralizing antibodies were not prognostic of outcomes. However, monitoring for ADAs with brodalumab and measuring titers with ixekizumab may be of value clinically.
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Affiliation(s)
- Alexandra Norden
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Aislyn Oulee
- University of California Riverside School of Medicine, Riverside, CA, USA
| | | | | | - George Han
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Jashin J Wu
- Department of Dermatology, University of Miami Miller School of Medicine
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Mosch R, Guchelaar HJ. Immunogenicity of Monoclonal Antibodies and the Potential Use of HLA Haplotypes to Predict Vulnerable Patients. Front Immunol 2022; 13:885672. [PMID: 35784343 PMCID: PMC9249215 DOI: 10.3389/fimmu.2022.885672] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/24/2022] [Indexed: 01/14/2023] Open
Abstract
The use of monoclonal antibodies (mAbs) in the clinic has successfully expanded to treatment of cancer, viral infections, inflammations, and other indications. However, some of the classes of mAbs that are used in the clinic show the formation of anti-drug antibodies (ADAs) leading to loss of efficacy. This review describes ADA formation for the various mAbs, and its clinical effect. Lastly, this review considers the use of HLA-haplotypes as biomarkers to predict vulnerability of patients sensitive to formation of ADAs.
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38
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Hammel JH, Zatorski JM, Cook SR, Pompano RR, Munson JM. Engineering in vitro immune-competent tissue models for testing and evaluation of therapeutics. Adv Drug Deliv Rev 2022; 182:114111. [PMID: 35031388 PMCID: PMC8908413 DOI: 10.1016/j.addr.2022.114111] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/16/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022]
Abstract
Advances in 3D cell culture, microscale fluidic control, and cellular analysis have enabled the development of more physiologically-relevant engineered models of human organs with precise control of the cellular microenvironment. Engineered models have been used successfully to answer fundamental biological questions and to screen therapeutics, but these often neglect key elements of the immune system. There are immune elements in every tissue that contribute to healthy and diseased states. Including immune function will be essential for effective preclinical testing of therapeutics for inflammatory and immune-modulated diseases. In this review, we first discuss the key components to consider in designing engineered immune-competent models in terms of physical, chemical, and biological cues. Next, we review recent applications of models of immunity for screening therapeutics for cancer, preclinical evaluation of engineered T cells, modeling autoimmunity, and screening vaccine efficacy. Future work is needed to further recapitulate immune responses in engineered models for the most informative therapeutic screening and evaluation.
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Affiliation(s)
- Jennifer H. Hammel
- Fralin Biomedical Research Institute and Department of Biomedical Engineering and Mechanics, Virginia Tech, Roanoke, Virginia 24016, USA
| | - Jonathan M. Zatorski
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA
| | - Sophie R. Cook
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA
| | - Rebecca R. Pompano
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, USA,Department of Biomedical Engineering, University of Virginia; Charlottesville, Virginia 22904, USA,Carter Immunology Center and UVA Cancer Center, University of Virginia School of Medicine, Charlottesville, Virginia 22903
| | - Jennifer M. Munson
- Fralin Biomedical Research Institute and Department of Biomedical Engineering and Mechanics, Virginia Tech, Roanoke, Virginia 24016, USA
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39
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Zhang XT, Chen H, Shao W, Lin ZJ, Melhem M, Lu S. A competitive ligand-binding assay for the detection of neutralizing antibodies against dostarlimab (TSR-042). AAPS OPEN 2021. [DOI: 10.1186/s41120-021-00039-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractDostarlimab is a humanized anti–PD-1 monoclonal antibody. Dostarlimab (JEMPERLI; TSR-042) was recently approved in the USA and in the EU. The presence of neutralizing antibodies (NAbs) is a cause for concern because they block the therapeutic function of the antibody and reduce drug efficacy. Therefore, programs developing therapeutic biologics need to develop and validate assays that adequately assess the presence of NAbs in the serum of patients treated with biologic therapies. Presented here is the development and validation of a competitive ligand-binding assay that specifically detects anti-dostarlimab NAbs in human serum. Precision, sensitivity, hook effect, selectivity, assay robustness, stabilities, and system suitability were evaluated. In addition, drug tolerance of the assay with the implementation of a drug removal process was investigated. The cut point factor for the detection of NAbs in human serum at a 1% false-positive rate was determined. The assay’s precision, sensitivity, hook effect, selectivity, robustness, and drug interference were tested and found to be acceptable. With system suitability and stability established, this assay has been used to evaluate NAbs to guide the development of dostarlimab.Trial registration: Clinicaltrials.gov, NCT02715284. Registered 9 March 2016
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40
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Albader F, Golovics PA, Gonczi L, Bessissow T, Afif W, Lakatos PL. Therapeutic drug monitoring in inflammatory bowel disease: The dawn of reactive monitoring. World J Gastroenterol 2021; 27:6231-6247. [PMID: 34712029 PMCID: PMC8515794 DOI: 10.3748/wjg.v27.i37.6231] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/08/2021] [Accepted: 08/31/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that significantly affects the quality of life of its patients. Biologic drugs have been the mainstay treatment in the management of IBD patients but despite their significant contribution, there remains a proportion of patients that do not respond or lose response to treatment. Therapeutic drug monitoring (TDM) involves measuring levels of serum drug concentrations and anti-drug antibodies. TDM of biologic drugs initially emerged to understand treatment failure in other immune mediated inflammatory diseases. This was then introduced in IBD to rationalize primary non-response or secondary loss of response, given that low serum drug concentrations or the formation of anti-drug antibodies are variably associated with treatment failure. The aim of this narrative review is to provide an overview regarding the current use of TDM in clinical practice and to present the evidence available regarding its use in both proactive and reactive clinical settings in preventing and managing treatment failure. This review also presents the existing evidence regarding the association of various clinical outcomes with specific thresholds of drug concentrations, in everyday practice. A narrative review of published articles and conference abstracts regarding the use of TDM in IBD management, through an electronic search using PubMed and ScienceDirect. TDM has proven to be superior and more cost effective in guiding management of patients with treatment failure compared to empiric dose escalation or change in treatment. Despite a trend towards an association between clinical outcomes and drug concentrations, proactive TDM based strategies have not been shown to achieve clear benefit in long-term outcomes. In the clinical setting, TDM has proven to be useful in managing IBD patients, and its use in the reactive setting, as an additional tool to help manage patients with treatment failure, is being promoted as newer guidelines and consensus groups implement TDM as part of the management plan.
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Affiliation(s)
- Farah Albader
- Department of Internal Medicine, McGill University, Montreal H3G1A4, Quebec, Canada
| | - Petra Anna Golovics
- Division of Gastroenterology, Hungarian Defence Forces, Medical Centre, Budapest H-1062, Hungary
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Lorant Gonczi
- First Department of Medicine, Semmelweis University, Budapest H-1083, Hungary
| | - Talat Bessissow
- Division of Gastroenterology, McGill University Health Centre, Montreal H3G 1A4, Quebec, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University, Montreal H3G 1A4, Quebec, Canada
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41
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Peters S, Galle PR, Bernaards CA, Ballinger M, Bruno R, Quarmby V, Ruppel J, Vilimovskij A, Wu B, Sternheim N, Reck M. Evaluation of atezolizumab immunogenicity: Efficacy and safety (Part 2). Clin Transl Sci 2021; 15:141-157. [PMID: 34582105 PMCID: PMC8742640 DOI: 10.1111/cts.13149] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/07/2021] [Accepted: 08/24/2021] [Indexed: 01/10/2023] Open
Abstract
Antibody therapeutics can be associated with unwanted immune responses resulting in the development of anti‐drug antibodies (ADA). Optimal methods to evaluate the potential effects of ADA on clinical outcomes in oncology are not well established. In this study, we assessed efficacy and safety, based on ADA status, in patients from over 10 clinical trials that evaluated the immune checkpoint inhibitor atezolizumab as a single agent or as combination therapy for several types of advanced cancers. ADA can only be observed post randomization, and imbalances in baseline prognostic factors can confound the interpretation of ADA impact. We applied methodology to account for the confounding effects of baseline clinical characteristics and survivorship bias on efficacy. Adjusted meta‐analyses revealed that despite numerical differences in overall survival and progression‐free survival between ADA‐positive and ADA‐negative patients from some studies, ADA‐positive patients from studies with an overall treatment effect derived benefit from atezolizumab, compared with their adjusted controls. Based on large, pooled populations from atezolizumab monotherapy or combination studies, unadjusted descriptive analyses did not identify a clear relationship between ADA status and frequency or severity of adverse events. Data also suggested that any ADA impact is not driven by neutralizing activity. Collectively, this exploratory analysis suggests that the potential for ADA development should not impact treatment decisions with atezolizumab.
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Affiliation(s)
- Solange Peters
- Oncology Department - CHUV, Lausanne University, Lausanne, Switzerland
| | - Peter R Galle
- Department of Internal Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Coen A Bernaards
- Product Development Biometrics, Genentech, Inc, South San Francisco, California, USA
| | - Marcus Ballinger
- Product Development Oncology, Genentech, Inc, South San Francisco, California, USA
| | - René Bruno
- Clinical Pharmacology, Genentech-Roche, Marseille, France
| | - Valerie Quarmby
- BioAnalytical Sciences, Genentech Inc, South San Francisco, California, USA
| | - Jane Ruppel
- BioAnalytical Sciences, Genentech Inc, South San Francisco, California, USA
| | | | - Benjamin Wu
- Department of Clinical Pharmacology, Genentech Inc, South San Francisco, California, USA
| | - Nitzan Sternheim
- Product Development Regulatory, Genentech Inc, South San Francisco, California, USA
| | - Martin Reck
- Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
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42
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Jiang AL, Breder CD, Chang LC. Investigation of Factors Associated with Immunogenicity Labeling Updates and Characteristics of Biologics License Applications. Clin Pharmacol Ther 2021; 110:1381-1388. [PMID: 34383294 DOI: 10.1002/cpt.2393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 07/26/2021] [Indexed: 11/12/2022]
Abstract
Immunogenicity, the potential to elicit an anti-drug immune response, is a critical concern in developing biological products, but its consequences are difficult to predict with animal studies. The aims of the present study are to investigate the evolution of immunogenicity information in labeling and to identify attributes associated with immunogenicity labeling updates. Biologics License Applications (BLAs) approved by the Center for Drug Evaluation and Research, United States Food and Drug Administration between 2008 and 2017 were studied. A majority of BLAs described the incidence/prevalence of anti-drug antibodies (ADAs) (94.9%) and neutralizing antibodies (NAbs) (68.4%) in their original labeling documents. However, less than one-third of the BLAs mentioned the impact of ADAs/NAbs in the original (20.3%) and most recent (29.1%) labeling documents. BLAs with a priority review status (57.4% versus 33.3%), orphan designation (61.5% versus 34.2%), or a mention of ADA impact in the latest label (69.6% versus 38.9%) had higher percentages of applications with postmarketing requirements (PMRs) directly related to immunogenicity concerns in comparison with applications without those characteristics. Among the BLAs with updated immunogenicity information, the mean time to the first update was 1077 days, while that for BLAs with accelerated approval was shorter (709.1 ± 492.2 days versus 1173.8 ± 661.8 days). The results suggest that there is a substantial amount of critical information lacking in the original labeling documents and an overdependence on PMRs for more evidence. Additional efforts should be made to investigate the impact of ADAs to provide timely information for improved patient care.
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Affiliation(s)
- Ai-Lei Jiang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Christopher D Breder
- Advanced Academic Programs, Krieger School of Arts and Sciences, Johns Hopkins University, Washington, DC, USA
| | - Lin-Chau Chang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
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43
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Parikh CR, Ponnampalam JK, Seligmann G, Coelewij L, Pineda-Torra I, Jury EC, Ciurtin C. Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults. Ther Adv Musculoskelet Dis 2021; 13:1759720X211002685. [PMID: 34188697 PMCID: PMC8212384 DOI: 10.1177/1759720x211002685] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 02/12/2021] [Indexed: 12/15/2022] Open
Abstract
The treatment of inflammatory arthritis has been revolutionised by the
introduction of biologic treatments. Many biologic agents are currently licensed
for use in both paediatric and adult patients with inflammatory arthritis and
contribute to improved disease outcomes compared with the pre-biologic era.
However, immunogenicity to biologic agents, characterised by an immune reaction
leading to the production of anti-drug antibodies (ADAs), can negatively impact
the therapeutic efficacy of biologic drugs and induce side effects to treatment.
This review explores for the first time the impact of immunogenicity against all
licensed biologic treatments currently used in inflammatory arthritis across
age, and will examine any significant differences between ADA prevalence, titres
and timing of development, as well as ADA impact on therapeutic drug levels,
clinical efficacy and side effects between paediatric and adult patients. In
addition, we will investigate factors associated with differences in
immunogenicity across biologic agents used in inflammatory arthritis, and their
potential therapeutic implications.
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Affiliation(s)
- Chinar R Parikh
- Centre for Adolescent Rheumatology versus Arthritis, University College London, London, UK
| | - Jaya K Ponnampalam
- Centre for Adolescent Rheumatology versus Arthritis, University College London, London, UK
| | - George Seligmann
- Centre for Adolescent Rheumatology versus Arthritis, University College London, London, UK
| | - Leda Coelewij
- Centre for Rheumatology Research, University College London, London, UK
| | - Ines Pineda-Torra
- Centre for Cardiometabolic and Vascular Science, University College London, London, UK
| | - Elizabeth C Jury
- Centre for Rheumatology Research, University College London, London, UK
| | - Coziana Ciurtin
- Centre for Adolescent Rheumatology Versus Arthritis, University College London, 3rd Floor Central, 250 Euston Road, London NW1 2PG, UK
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In vitro immunogenicity prediction: bridging between innate and adaptive immunity. Bioanalysis 2021; 13:1071-1081. [PMID: 34124935 DOI: 10.4155/bio-2021-0077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Development of antidrug antibodies (ADAs) is an undesirable potential outcome of administration of biotherapeutics and involves the innate and adaptive immune systems. ADAs can have detrimental clinical consequences: they can reduce biotherapeutic efficacy or produce adverse events. Because animal models are considered poor predictors of immunogenicity in humans, in vitro assays with human innate and adaptive immune cells are commonly used alternatives that can reveal cell-mediated unwanted immune responses. Multiple methods have been developed to assess the immune cell response following exposure to biotherapeutics and estimate the potential immunogenicity of biotherapeutics. This review highlights the role of innate and adaptive immune cells as the drivers of immunogenicity and summarizes the use of these cells in assays to predict clinical ADA.
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Walters RR, Boucher JF, De Toni F. Pharmacokinetics and Immunogenicity of Frunevetmab in Osteoarthritic Cats Following Intravenous and Subcutaneous Administration. Front Vet Sci 2021; 8:687448. [PMID: 34179175 PMCID: PMC8222533 DOI: 10.3389/fvets.2021.687448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/27/2021] [Indexed: 11/21/2022] Open
Abstract
Osteoarthritis and other degenerative joint diseases are common causes of chronic pain in cats. Frunevetmab is a felinized monoclonal antibody that binds to nerve growth factor (NGF) and provides relief from pain by blocking the receptor-mediated signaling cascade induced by NGF. Results from three studies were combined to provide an overview of frunevetmab pharmacokinetics (PK) and immunogenicity. The objective of the first study was to establish the pharmacokinetic parameters resulting from intravenous (IV) and subcutaneous (SC) administration of frunevetmab to the feline patient population at 3 mg/kg. Ten adult cats with naturally-occurring osteoarthritis were administered frunevetmab in a crossover design at 28 day intervals. Non-compartmental pharmacokinetic analysis of the plasma concentration-time data showed that the half-life was 10.1 ± 1.9 days after IV dosing and the SC bioavailability was 60.3 ± 15.8% with maximum drug levels observed at 3-7 days after dosing. Plasma samples were collected at ~28 days after dosing during two field safety and effectiveness studies of cats with degenerative joint disease. The doses ranged from 1.0 to 2.8 mg/kg; 2 or 3 doses were administered either SC/IV, SC/SC, or SC/SC/SC. The data from these studies along with the data from the laboratory pharmacokinetic study were analyzed using non-linear mixed-effects (NLME) modeling. The model closely predicted the trough concentrations from the two field studies, including the IV treatment in the pilot field study. The trough concentrations were predicted to be close to steady-state after 2 doses. A second objective was to determine the incidence and clinical relevance of frunevetmab immunogenicity. A three-tier anti-drug antibody assay (screen, confirm, titer) was developed and validated. Immunogenicity was assessed in 259 frunevetmab-treated animals enrolled in the two field studies. Only 4 of these animals (1.5%) appeared to develop immunogenicity to frunevetmab. None of the four exhibited adverse events attributed to immunogenicity and no impact on drug levels or efficacy was observed in three of the animals. In the placebo animals, 2.3% (3/131) appeared to develop treatment-emergent immunogenicity. Overall, frunevetmab administration resulted in a very low incidence of treatment-emergent immunogenicity with no safety findings and minimal effect on drug exposure and efficacy.
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Affiliation(s)
| | | | - Flavia De Toni
- Veterinary Medicine Research and Development, Zoetis, Kalamazoo, MI, United States
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Malik PRV, Temrikar ZH, Chelle P, Edginton AN, Meibohm B. Pediatric Dose Selection for Therapeutic Proteins. J Clin Pharmacol 2021; 61 Suppl 1:S193-S206. [PMID: 34185910 DOI: 10.1002/jcph.1829] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 01/26/2021] [Indexed: 12/12/2022]
Abstract
In selecting optimal dosing regimens in support of the clinical use of monoclonal antibodies and other therapeutic proteins in pediatric indications, the unique pharmacokinetic properties of this class of biologics, as well as the underlying physiologic and pathophysiologic processes and their modulation by childhood growth and development, needs to be appreciated. During drug development, first-in-pediatric dose selection is a capstone event in the pediatric investigation plan that relies heavily on extrapolation of pharmacokinetic and pharmacodynamic data from adult to pediatric populations. It is facilitated by combinations of pharmacometric approaches, including allometry, physiologically based pharmacokinetic modeling, and population pharmacokinetic analyses, although data on reliability and qualification of some of these tools in the context of therapeutic proteins are still limited but emerging. Presented data suggest nonlinear relationships between body weight and both clearance and volume of distribution for therapeutic proteins in pediatric populations, with allometric exponents of 0.75 and 0.8, respectively. For newborns and infants (<1 year), even higher nonlinearity seems to occur. Translation of the quantitative characterization of the pediatric pharmacokinetics of therapeutic proteins into dosing regimens for the drug label requires compromising between precision dosing and clinical practicability, with tiered dosing algorithms based on size or age strata being the currently most frequently applied methodology.
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Affiliation(s)
- Paul R V Malik
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Zaid H Temrikar
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Pierre Chelle
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Andrea N Edginton
- School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Golam Kibria M, Akazawa-Ogawa Y, Hagihara Y, Kuroda Y. Immune response with long-term memory triggered by amorphous aggregates of misfolded anti-EGFR V HH-7D12 is directed against the native V HH-7D12 as well as the framework of the analogous V HH-9G8. Eur J Pharm Biopharm 2021; 165:13-21. [PMID: 33971271 DOI: 10.1016/j.ejpb.2021.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023]
Abstract
We previously demonstrated that amorphous aggregates of misfolded VHH-7D12 antibodies (VHH-Mis), a potential anti-EGFR drug, can generate a robust serum IgG response. Here we investigate the immunogenic nature, especially the specificity of the immune response induced by VHH-Mis. To this end, we used two natively folded and 77% identical anti-EGFR VHHs (VHH-7D12 and VHH-9G8) that possess a common framework but distinct complementarity determining regions (CDRs). In 60% of mice immunized with VHH-Mis, the anti-VHH-7D12 IgG titer was stronger than the anti-VHH-9G8 titer (Group-1). In the remaining mice (40%; Group-2), the anti-VHH-7D12 and anti-VHH-9G8 titer were almost identical. We rationalized these results by hypothesizing that mice in Group-1 produced IgG mostly against the VHH-7D12's CDRs, whereas in Group-2 mice, they targeted the VHH's framework. The IgG specificity against VHH-7D12 and VHH-9G8 was essentially unchanged over 17 weeks in both groups. Further, in all mice (Group-1&2) re-immunized with native VHH-7D12, the IgG titer against VHH-7D12 increased sharply but not against VHH-9G8. On the other hand, none of the three Group-1 mice re-immunized with native VHH-9G8 showed immunogenicity against VHH-7D12 nor VHH-9G8. Whereas, in Group-2 mice (three/three) re-immunized with VHH-9G8, the IgG titers against both VHHs increased but slowly. Flow-cytometric studies showed that VHH-Mis immunized mice generated a higher number of effector and central memory T-cells. Overall, these observations indicate that amorphous aggregates made of a misfolded VHH can induce serum IgG against its natively folded self and analogous VHHs having a similar framework but distinct CDRs. Furthermore, a robust long-term immune response with memory was established against its natively folded self but with a nil-to-moderate immune response against natively folded VHH analogs.
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Affiliation(s)
- Md Golam Kibria
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei-shi, Tokyo 184-8588, Japan
| | - Yoko Akazawa-Ogawa
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan
| | - Yoshihisa Hagihara
- Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan
| | - Yutaka Kuroda
- Department of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei-shi, Tokyo 184-8588, Japan.
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Privitera G, Pugliese D, Onali S, Petito V, Scaldaferri F, Gasbarrini A, Danese S, Armuzzi A. Combination therapy in inflammatory bowel disease - from traditional immunosuppressors towards the new paradigm of dual targeted therapy. Autoimmun Rev 2021; 20:102832. [PMID: 33866066 DOI: 10.1016/j.autrev.2021.102832] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 02/15/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Combining immunosuppressors has been proposed as a strategy to enhance treatment efficacy in Inflammatory Bowel Disease (IBD). AIM To summarize current evidence on combinations of targeted therapies with traditional immunosuppressors or with other targeted therapies. METHODS A literature search on PubMed and Medline databases was performed to identify relevant articles. RESULTS Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy with both agents in inducing remission in Crohn's Disease and Ulcerative colitis. Data on other combinations of other biologics and traditional immunosuppressors is lacking or show conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis, as an alternative to thiopurines. Dual Targeted Therapy, which is the combination of 2 targeted therapies, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Combinations with thiopurines are associated with an increased risk of infections and lymphoma. Data on other combinations is scarcer, but no specific safety issue has emerged so far. CONCLUSIONS Combination therapies seem to be effective in selected patients, with an overall acceptable safety profile.
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Affiliation(s)
- Giuseppe Privitera
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Daniela Pugliese
- CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
| | - Sara Onali
- Gastroenterology Unit, University Hospital of Cagliari, Department of Science and Public Health, University of Cagliari, Italy
| | - Valentina Petito
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
| | - Franco Scaldaferri
- CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
| | - Antonio Gasbarrini
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano, Milan 20089, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
| | - Alessandro Armuzzi
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy.
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Bray-French K, Hartman K, Steiner G, Marban-Doran C, Bessa J, Campbell N, Martin-Facklam M, Stubenrauch KG, Solier C, Singer T, Ducret A. Managing the Impact of Immunogenicity in an Era of Immunotherapy: From Bench to Bedside. J Pharm Sci 2021; 110:2575-2584. [PMID: 33812888 DOI: 10.1016/j.xphs.2021.03.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/27/2021] [Accepted: 03/30/2021] [Indexed: 12/11/2022]
Abstract
Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness. This prompted the Roche Pharma Research and Early Development (pRED) Immunogenicity Working Group to establish an internal preclinical immunogenicity toolbox of in vitro/in vivo approaches and accompanying guidelines for a harmonized assessment and management of immunogenicity in early development. In this article, the complex factors influencing immunogenicity and their associated clinical ramifications are discussed to highlight the importance of an end-to-end approach conducted from lead optimization to clinical candidate selection. We then examine the impact of the resulting lead candidate categorization on the design and implementation of a multi-tiered ADA/immunogenicity assay strategy prior to phase I (entry into human) through early clinical development. Ultimately, the Immunogenicity Toolbox ensures that Roche pRED teams are equipped to address immunogenicity in a standardized manner, paving the way for lifesaving products with improved safety and efficacy.
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Affiliation(s)
- Katharine Bray-French
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Katharina Hartman
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Guido Steiner
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Céline Marban-Doran
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Juliana Bessa
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Neil Campbell
- Global Product Strategy, Pharma Division, F. Hoffmann-La Roche AG, Basel, Switzerland
| | - Meret Martin-Facklam
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Kay-Gunnar Stubenrauch
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Munich, Munich, Germany
| | - Corinne Solier
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Thomas Singer
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Axel Ducret
- Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
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50
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Heron CE, Ghamrawi RI, Balogh EA, Feldman SR. Immunogenicity of Biologic and Biosimilar Therapies for Psoriasis and Impact of Novel Immunoassays for Immunogenicity Detection. Am J Clin Dermatol 2021; 22:221-231. [PMID: 33169802 DOI: 10.1007/s40257-020-00569-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2020] [Indexed: 12/21/2022]
Abstract
Anti-drug antibodies (ADAs) may develop against originator biologic and biosimilar therapies used for the treatment of psoriasis and may be the cause of initial therapeutic non-response or diminished therapeutic response over time. Comparing immunogenicity between therapeutic agents is challenging owing to the variation in assays used for detection, among other reasons. Using the results of a PubMed search for psoriasis clinical trials disclosing the rates of ADAs for originator biologic and biosimilar therapies approved for the treatment of psoriasis within the last 5 years, this review discusses the rates and potential clinical impact of ADA formation in patients with psoriasis managed with originator biologic and biosimilar therapies, along with novel methods of ADA testing. Anti-drug antibodies are detectable in all biologic and biosimilar therapies approved for the treatment of psoriasis in the last 5 years, and the effect of ADAs on clinical response varies by agent. Novel immunoassays used for the detection of ADAs may have increased sensitivity compared with traditional assays, although the increased rate of detection may not correlate with decreased clinical response and the decision to test for the presence of ADAs may vary from patient to patient. Though ADA formation seems ubiquitous with the use of biologic agents for the treatment of psoriasis, the increased rates of ADAs detected by novel immunoassays may not necessarily correlate with decreased treatment efficacy.
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