1
|
de Graav GN, Udomkarnjananun S, Baan CC, Reinders MEJ, Roodnat JI, de Winter BCM, Hesselink DA. New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review. Ther Drug Monit 2025; 47:64-76. [PMID: 39570574 DOI: 10.1097/ftd.0000000000001275] [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: 07/30/2024] [Accepted: 08/31/2024] [Indexed: 11/22/2024]
Abstract
PURPOSE In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents. METHODS Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014-2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov . RESULTS Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies. CONCLUSIONS The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.
Collapse
Affiliation(s)
- Gretchen N de Graav
- Department of Internal Medicine, Division of Nephrology, Reinier de Graaf Gasthuis, Delft, the Netherlands
| | - Suwasin Udomkarnjananun
- Department of Medicine, Division of Nephrology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Carla C Baan
- Transplant Laboratory & Research Center, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Marlies E J Reinders
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
| | - Joke I Roodnat
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
| | - Brenda C M de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands ; and
| |
Collapse
|
2
|
Mahgoub M, Zand L. Recurrent FSGS Post-Kidney Transplantations: Where Do We Stand? Transplantation 2025:00007890-990000000-00988. [PMID: 39828914 DOI: 10.1097/tp.0000000000005335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Affiliation(s)
- Mohammed Mahgoub
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN
| | | |
Collapse
|
3
|
Hesen N, Anany M, Freidel A, Baker M, Siegmund D, Zaitseva O, Wajant H, Lang I. Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism. Bioengineered 2024; 15:2302246. [PMID: 38214443 PMCID: PMC10793706 DOI: 10.1080/21655979.2024.2302246] [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: 06/07/2023] [Accepted: 12/08/2023] [Indexed: 01/13/2024] Open
Abstract
Most anti-CD40 antibodies show robust agonism only upon binding to FcγR+ cells, such as B cells, macrophages, or DCs, but a few anti-CD40 antibodies display also strong intrinsic agonism dependent on the recognized epitope and/or isotype. It is worth mentioning, however, that also the anti-CD40 antibodies with intrinsic agonism can show a further increase in agonistic activity when bound by FcγR-expressing cells. Thus, conventional antibodies appear not to be sufficient to trigger the maximum possible CD40 activation independent from FcγR-binding. We proved here the hypothesis that oligomeric and oligovalent anti-CD40 antibody variants generated by genetic engineering display high intrinsic, thus FcγR-independent, agonistic activity. We generated tetra-, hexa- and dodecavalent variants of six anti-CD40 antibodies and a CD40-specific nanobody. All these oligovalent variants, even when derived of bivalent antagonistic anti-CD40 antibodies, showed strongly enhanced CD40 agonism compared to their conventional counterparts. In most cases, the CD40 agonism reached the maximum response induced by FcγR-bound anti-CD40 antibodies or membrane CD40L, the natural engager of CD40. In sum, our data show that increasing the valency of anti-CD40 antibody constructs by genetic engineering regularly results in molecules with high intrinsic agonism and level out the specific limitations of the parental antibodies.
Collapse
Affiliation(s)
- Nienke Hesen
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Mohamed Anany
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
- Department of Microbial Biotechnology, Institute of Biotechnology, National Research Center, Giza, Egypt
| | - Andre Freidel
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Mediya Baker
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Daniela Siegmund
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Olena Zaitseva
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Harald Wajant
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| | - Isabell Lang
- Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, WürzburgGermany
| |
Collapse
|
4
|
Iesari S, Nava FL, Zais IE, Coubeau L, Ferraresso M, Favi E, Lerut J. Advancing immunosuppression in liver transplantation: A narrative review. Hepatobiliary Pancreat Dis Int 2024; 23:441-448. [PMID: 38523030 DOI: 10.1016/j.hbpd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
Collapse
Affiliation(s)
- Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Francesca Laura Nava
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Ilaria Elena Zais
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Laurent Coubeau
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium; Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 55 Avenue Hippocrate, 1200 Brussels, Belgium
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy.
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium
| |
Collapse
|
5
|
Hou S, Yang B, Chen Q, Xu Y, Li H. Potential biomarkers of recurrent FSGS: a review. BMC Nephrol 2024; 25:258. [PMID: 39134955 PMCID: PMC11318291 DOI: 10.1186/s12882-024-03695-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS), a clinicopathological condition characterized by nephrotic-range proteinuria, has a high risk of progression to end-stage renal disease (ESRD). Meanwhile, the recurrence of FSGS after renal transplantation is one of the main causes of graft loss. The diagnosis of recurrent FSGS is mainly based on renal puncture biopsy transplants, an approach not widely consented by patients with early mild disease. Therefore, there is an urgent need to find definitive diagnostic markers that can act as a target for early diagnosis and intervention in the treatment of patients. In this review, we summarize the domestic and international studies on the pathophysiology, pathogenesis and earliest screening methods of FSGS and describe the functions and roles of specific circulating factors in the progression of early FSGS, in order to provide a new theoretical basis for early diagnosis of FSGS recurrence, as well as aid the exploration of therapeutic targets.
Collapse
Affiliation(s)
- Shuang Hou
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Bo Yang
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Yuan Xu
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
| | - Haiyang Li
- Hepatological surgery department, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
| |
Collapse
|
6
|
Shoji J, Goggins WC, Wellen JR, Cunningham PN, Johnston O, Chang SS, Solez K, Santos V, Larson TJ, Takeuchi M, Wang X. Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study. Transplantation 2024; 108:1782-1792. [PMID: 39042770 PMCID: PMC11262731 DOI: 10.1097/tp.0000000000004985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 01/08/2024] [Accepted: 01/29/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.
Collapse
MESH Headings
- Humans
- Kidney Transplantation/adverse effects
- Glomerulosclerosis, Focal Segmental/drug therapy
- Glomerulosclerosis, Focal Segmental/immunology
- Male
- Female
- Middle Aged
- Adult
- Immunosuppressive Agents/therapeutic use
- Immunosuppressive Agents/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Treatment Outcome
- Recurrence
- Tacrolimus/therapeutic use
- Tacrolimus/adverse effects
- Graft Survival/drug effects
- Drug Therapy, Combination
- Adrenal Cortex Hormones/therapeutic use
- Secondary Prevention/methods
- Kidney Failure, Chronic/surgery
- Kidney Failure, Chronic/prevention & control
- Kidney Failure, Chronic/etiology
Collapse
Affiliation(s)
- Jun Shoji
- Division of Transplant Nephrology, University of California San Francisco, San Francisco, CA
| | - William C. Goggins
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
| | - Jason R. Wellen
- Division of Transplantation, Department of Surgery, Washington University in St Louis, St Louis, MO
| | | | - Olwyn Johnston
- Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Shirley S. Chang
- Division of Nephrology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Erie County Medical Center, Buffalo, NY
| | - Kim Solez
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Vicki Santos
- Astellas Pharma Global Development Inc, Northbrook, IL
| | | | | | - Xuegong Wang
- Astellas Pharma Global Development Inc, Northbrook, IL
| |
Collapse
|
7
|
Asano R, Nakakido M, Pérez JF, Ise T, Caaveiro JMM, Nagata S, Tsumoto K. Crystal structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab. Biochem Biophys Res Commun 2024; 714:149969. [PMID: 38657446 DOI: 10.1016/j.bbrc.2024.149969] [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: 04/17/2024] [Accepted: 04/17/2024] [Indexed: 04/26/2024]
Abstract
CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.
Collapse
Affiliation(s)
- Risa Asano
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Makoto Nakakido
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan; Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan.
| | - Jorge Fernández Pérez
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Tomoko Ise
- Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Jose M M Caaveiro
- Department of Protein Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Nagata
- Laboratory of Antibody Design, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Kouhei Tsumoto
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan; Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo, Japan; Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, Tokyo, Japan; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| |
Collapse
|
8
|
Grosu-Bularda A, Hodea FV, Zamfirescu D, Stoian A, Teodoreanu RN, Lascăr I, Hariga CS. Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation? J Pers Med 2024; 14:322. [PMID: 38541064 PMCID: PMC10971463 DOI: 10.3390/jpm14030322] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/12/2024] [Accepted: 03/18/2024] [Indexed: 11/12/2024] Open
Abstract
The field of transplantation, including the specialized area of vascularized composite allotransplantation (VCA), has been transformed since the first hand transplant in 1998. The major challenge in VCA comes from the need for life-long immunosuppressive therapy due to its non-vital nature and a high rate of systemic complications. Ongoing research is focused on immunosuppressive therapeutic strategies to avoid toxicity and promote donor-specific tolerance. This includes studying the balance between tolerance and effector mechanisms in immune modulation, particularly the role of costimulatory signals in T lymphocyte activation. Costimulatory signals during T cell activation can have either stimulatory or inhibitory effects. Interfering with T cell activation through costimulation blockade strategies shows potential in avoiding rejection and prolonging the survival of transplanted organs. This review paper aims to summarize current data on the immunologic role of costimulatory blockade in the field of transplantation. It focuses on strategies that can be applied in vascularized composite allotransplantation, offering insights into novel methods for enhancing the success and safety of these procedures.
Collapse
Affiliation(s)
- Andreea Grosu-Bularda
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Florin-Vlad Hodea
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | | | | | - Răzvan Nicolae Teodoreanu
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Ioan Lascăr
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| | - Cristian Sorin Hariga
- Department 11, Discipline Plastic and Reconstructive Surgery, Bucharest Clinical Emergency Hospital, University of Medicine and Pharmacy Carol Davila, 050474 Bucharest, Romania; (A.G.-B.); (R.N.T.); (I.L.); (C.S.H.)
- Clinic of Plastic Surgery, Aesthetic and Reconstructive Microsurgery, Emergency Clinical Hospital Bucharest, 050474 Bucharest, Romania
| |
Collapse
|
9
|
Samant M, Ziemniak J, Paolini JF. First-in-Human Phase 1 Randomized Trial with the Anti-CD40 Monoclonal Antibody KPL-404: Safety, Tolerability, Receptor Occupancy, and Suppression of T-Cell-Dependent Antibody Response. J Pharmacol Exp Ther 2023; 387:306-314. [PMID: 37699709 DOI: 10.1124/jpet.123.001771] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/04/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
Blockade of the cluster of differentiation 40 (CD40)-CD40L interaction has potential for treating autoimmune diseases and preventing graft rejection. This first-in-human, randomized, double-blind, placebo-controlled study (NCT04497662) evaluated safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the humanized anti-CD40 monoclonal antibody KPL-404. Healthy volunteers were randomized to one of two single-ascending-dose groups: single intravenous KPL-404 dose 0.03, 0.3, 1, 3, or 10 mg/kg or single subcutaneous KPL-404 dose 1 or 5 mg/kg. There were no dose-limiting or dose-related safety findings. Nonlinear dose-dependent changes in various pharmacokinetic parameters were identified following the range of intravenous doses. At the 10 mg/kg intravenous dose level, the t1/2 was approximately 7 days, and full receptor occupancy was observed through Day 71, with complete suppression of T-cell-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) challenge on Day 1 and rechallenge on Day 29 through Day 57. With KPL-404 5 mg/kg subcutaneously, full receptor occupancy was observed through Day 43, with complete suppression of TDAR through at least Day 29. Antidrug antibodies to KPL-404 were suppressed for 57 days with 10 mg/kg intravenously and for 50 days with 5 mg/kg subcutaneously, further confirming prolonged target engagement and pharmacodynamics. These findings support continued investigation of KPL-404 intravenous and subcutaneous administration in a broad range of indications. SIGNIFICANCE STATEMENT: This first-in-human clinical trial of KPL-404, a fully humanized IgG4 monoclonal antibody, was designed with two independent (by route of administration) placebo-controlled single-ascending-dose-level groups, one with four intravenous single-dose cohorts and another with two subcutaneous single-dose cohorts. The pharmacokinetic profile, duration of full CD40 receptor occupancy, and magnitude and duration of memory immune response suppression observed confirm pharmacodynamic activity regardless of administration route. These data provide evidence that chronic KPL-404 dosing regimens (intravenous or subcutaneous) could be practical.
Collapse
Affiliation(s)
- Manoj Samant
- Kiniksa Pharmaceuticals, Lexington, Massachusetts
| | | | | |
Collapse
|
10
|
Qayyum S, Shahid K. Comparative Safety and Efficacy of Immunosuppressive Regimens Post-kidney Transplant: A Systematic Review. Cureus 2023; 15:e43903. [PMID: 37746361 PMCID: PMC10512192 DOI: 10.7759/cureus.43903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Immunosuppressive agents are used post-organ transplant to prevent acute rejection and graft losses. Tacrolimus, the most widely used immunosuppressive agent for kidney transplant recipients, has unfavorable side effects such as new-onset diabetes after transplant, nephrotoxicity, and electrolyte imbalances. Other drug groups such as the mammalian target of rapamycin (mTOR) inhibitors, belatacept, and bleselumab have been used to either substitute calcineurin inhibitors or reduce their exposure. This systematic analysis reviews evidence from randomized controlled trials to compare the safety and efficacy of various immunosuppressive regimens for kidney transplant recipients. An in-depth methodical search was conducted across PubMed, Cochrane Library, and Mendeley. PRISMA 2020 guidelines were followed for this study. Randomized controlled trials comparing varying regimens were included in this study. While there was no difference in safety and efficacy between once-daily and twice-daily tacrolimus, mTOR inhibitors showed to be a viable option for a reduced tacrolimus exposure regimen. Calcineurin inhibitor avoidance and early steroid withdrawal regimens both showed increased rates of rejection. Based on these findings, a regimen containing once-daily tacrolimus and an mTOR inhibitor with or without corticosteroid is a viable immunosuppressive regimen post-kidney transplant. Further trials, especially ones with longer follow-up periods, are needed to explore these regimens' long-term safety and efficacy.
Collapse
Affiliation(s)
- Shahid Qayyum
- Nephrology, Diaverum Dialysis Center, Wadi Al Dawasir, SAU
| | - Kamran Shahid
- Internal Medicine/Family Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| |
Collapse
|
11
|
Shi T, Burg AR, Caldwell JT, Roskin KM, Castro-Rojas CM, Chukwuma PC, Gray GI, Foote SG, Alonso JA, Cuda CM, Allman DA, Rush JS, Regnier CH, Wieczorek G, Alloway RR, Shields AR, Baker BM, Woodle ES, Hildeman DA. Single-cell transcriptomic analysis of renal allograft rejection reveals insights into intragraft TCR clonality. J Clin Invest 2023; 133:e170191. [PMID: 37227784 PMCID: PMC10348771 DOI: 10.1172/jci170191] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/23/2023] [Indexed: 05/27/2023] Open
Abstract
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single-cell RNA transcriptomic and TCR-α/β sequencing on rBx from patients with ACR under differing IS drugs: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within expanded CD8+ T cell clonotypes (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCR-α/β cDNAs from CD8EXP into Jurkat 76 cells (TCR-/-) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful antirejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps for improving detection, assessment, and treatment of rejection.
Collapse
Affiliation(s)
- Tiffany Shi
- Division of Immunobiology and
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Medical Scientist Training Program and
| | - Ashley R. Burg
- Division of Immunobiology and
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | | | - Krishna M. Roskin
- Division of Immunobiology and
- Divison of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | | | - P. Chukwunalu Chukwuma
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - George I. Gray
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Sara G. Foote
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Jesus A. Alonso
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - Carla M. Cuda
- Northwestern University, Feinberg School of Medicine, Department of Medicine, Division of Rheumatology, Chicago, Illinois, USA
| | - David A. Allman
- University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - James S. Rush
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Catherine H. Regnier
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Grazyna Wieczorek
- Novartis Institutes for Biomedical Research, Immunology Disease Area, Basel, Switzerland
| | - Rita R. Alloway
- Division of Nephrology and Hypertension, Department of Internal Medicine, and
| | - Adele R. Shields
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Brian M. Baker
- Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA
| | - E. Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - David A. Hildeman
- Division of Immunobiology and
- Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
- Medical Scientist Training Program and
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
12
|
Marengo M, Migliori M, Merlotti G, Fabbrini P, Panichi V, Cantaluppi V. Role of the CD40-CD40 Ligand Pathway in Cardiovascular Events, Neurological Alterations, and Other Clinical Complications of Chronic Hemodialysis Patients: Protective Role of Adsorptive Membranes. Blood Purif 2023; 52 Suppl 1:27-42. [PMID: 37331328 PMCID: PMC10568606 DOI: 10.1159/000530808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/16/2023] [Indexed: 06/20/2023]
Abstract
Despite the recent advances in dialysis technology, mortality rate of chronic uremic patients still remains excessively high: of note, in comparison to age- and sex-matched healthy controls, this frail population shows a higher incidence of infections, cancer, cognitive decline, and, in particular, major adverse cardiovascular events (MACE) that represent nowadays the first cause of mortality. Several traditional and nontraditional factors contribute to this increased risk for MACE and accelerated cellular senescence: among these, inflammation has been shown to play a key role. The costimulatory pathway CD40-CD40 Ligand (CD40L) is harmfully activated during inflammation and uremia-associated clinical complications: in particular, the soluble form of CD40L (sCD40L) can bind to the CD40 receptor triggering a cascade of detrimental pathways in immune and nonimmune cells. In this narrative review, we summarize the current concepts of the biological role of the CD40-CD40L pathway in uremia-associated organ dysfunction, focusing on the above-described main causes of mortality. Moreover, we discuss the interaction of the CD40-CD40L pathway with extracellular vesicles, microparticles recently identified as new uremic toxins. The biological effects of sCD40L in MACE, cognitive decline, infections, and cancer will be also briefly commented. Last, based on recent studies and ongoing clinical trials, we herein describe the modulatory activity of adsorptive dialysis membranes in polymethylmethacrylate on CD40-CD40L detrimental activation.
Collapse
Affiliation(s)
| | | | - Guido Merlotti
- Department of Translational Medicine (DIMET), Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, University of Piemonte Orientale (UPO), Novara, Italy,
| | - Paolo Fabbrini
- Nephrology and Dialysis Unit, ASST Nord Milano, "Bassini" Hospital, Cinisello Balsamo, Italy
| | - Vincenzo Panichi
- Nephrology, Dialysis and Kidney Transplantation Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine (DIMET), Nephrology and Kidney Transplantation Unit, "Maggiore della Carità" University Hospital, University of Piemonte Orientale (UPO), Novara, Italy
| |
Collapse
|
13
|
Shi T, Burg AR, Caldwell JT, Roskin K, Castro-Rojas CM, Chukwuma PC, Gray GI, Foote SG, Alonso J, Cuda CM, Allman DA, Rush JS, Regnier CH, Wieczorek G, Alloway RR, Shields AR, Baker BM, Woodle ES, Hildeman DA. Single cell transcriptomic analysis of renal allograft rejection reveals novel insights into intragraft TCR clonality. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.08.524808. [PMID: 36798151 PMCID: PMC9934650 DOI: 10.1101/2023.02.08.524808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding. We performed combined single cell RNA transcriptomic and TCRα/β sequencing on rBx from patients with ACR under differing immunosuppression (IS): tacrolimus, iscalimab, and belatacept. TCR analysis revealed a highly restricted CD8 + T cell clonal expansion (CD8 EXP ), independent of HLA mismatch or IS type. Subcloning of TCRα/β cDNAs from CD8 EXP into Jurkat76 cells (TCR -/- ) conferred alloreactivity by mixed lymphocyte reaction. scRNAseq analysis of CD8 EXP revealed effector, memory, and exhausted phenotypes that were influenced by IS type. Successful anti-rejection treatment decreased, but did not eliminate, CD8 EXP , while CD8 EXP were maintained during treatment-refractory rejection. Finally, most rBx-derived CD8 EXP were also observed in matching urine samples. Overall, our data define the clonal CD8 + T cell response to ACR, providing novel insights to improve detection, assessment, and treatment of rejection.
Collapse
|
14
|
Farshbafnadi M, Razi S, Rezaei N. Transplantation. Clin Immunol 2023. [DOI: 10.1016/b978-0-12-818006-8.00008-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
|
15
|
Kervella D, Blancho G. New immunosuppressive agents in transplantation. Presse Med 2022; 51:104142. [PMID: 36252821 DOI: 10.1016/j.lpm.2022.104142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 09/29/2022] [Indexed: 11/24/2022] Open
Abstract
Immunosuppressive agents have enabled the development of allogenic transplantation during the last 40 years, allowing considerable improvement in graft survival. However, several issues remain such as the nephrotoxicity of calcineurin inhibitors, the cornerstone of immunosuppressive regimens and/or the higher risk of opportunistic infections and cancers. Most immunosuppressive agents target T cell activation and may not be efficient enough to prevent allo-immunization in the long term. Finally, antibody mediated rejection due to donor specific antibodies strongly affects allograft survival. Many drugs have been tested in the last decades, but very few have come to clinical use. The most recent one is CTLA4-Ig (belatacept), a costimulation blockade molecule that targets the second signal of T cell activation and is associated with a better long term kidney function than calcineurin inhibitors, despite an increased risk of acute cellular rejection. The research of new maintenance long-term immunosuppressive agents focuses on costimulation blockade. Agents inhibiting CD40-CD40 ligand interaction may enable a good control of both T cells and B cells responses. Anti-CD28 antibodies may promote regulatory T cells. Agents targeting this costimulation pathways are currently evaluated in clinical trials. Immunosuppressive agents for ABMR treatment are scarce since anti-CD20 agent rituximab and proteasome inhibitor bortezomib have failed to demonstrate an interest in ABMR. New drugs focusing on antibodies removal (imlifidase), B cell and plasmablasts (anti-IL-6/IL-6R, anti-CD38…) and complement inhibition are in the pipeline, with the challenge of their evaluation in such a heterogeneous pathology.
Collapse
Affiliation(s)
- Delphine Kervella
- CHU Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, ITUN, Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France
| | - Gilles Blancho
- CHU Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, ITUN, Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France.
| |
Collapse
|
16
|
Lang I, Zaitseva O, Wajant H. FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies. Int J Mol Sci 2022; 23:12869. [PMID: 36361658 PMCID: PMC9655775 DOI: 10.3390/ijms232112869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 03/14/2024] Open
Abstract
Inhibitory targeting of the CD40L-CD40 system is a promising therapeutic option in the field of organ transplantation and is also attractive in the treatment of autoimmune diseases. After early complex results with neutralizing CD40L antibodies, it turned out that lack of Fcγ receptor (FcγR)-binding is the crucial factor for the development of safe inhibitory antibodies targeting CD40L or CD40. Indeed, in recent years, blocking CD40 antibodies not interacting with FcγRs, has proven to be well tolerated in clinical studies and has shown initial clinical efficacy. Stimulation of CD40 is also of considerable therapeutic interest, especially in cancer immunotherapy. CD40 can be robustly activated by genetically engineered variants of soluble CD40L but also by anti-CD40 antibodies. However, the development of CD40L-based agonists is biotechnologically and pharmacokinetically challenging, and anti-CD40 antibodies typically display only strong agonism in complex with FcγRs or upon secondary crosslinking. The latter, however, typically results in poorly developable mixtures of molecule species of varying stoichiometry and FcγR-binding by anti-CD40 antibodies can elicit unwanted side effects such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of CD40 expressing immune cells. Here, we summarize and compare strategies to overcome the unwanted target cell-destroying activity of anti-CD40-FcγR complexes, especially the use of FcγR type-specific mutants and the FcγR-independent cell surface anchoring of bispecific anti-CD40 fusion proteins. Especially, we discuss the therapeutic potential of these strategies in view of the emerging evidence for the dose-limiting activities of systemic CD40 engagement.
Collapse
Affiliation(s)
| | | | - Harald Wajant
- Department of Internal Medicine II, Division of Molecular Internal Medicine, University Hospital Würzburg, Auvera Haus, Grombühlstrasse 12, 97080 Würzburg, Germany
| |
Collapse
|
17
|
Strohm L, Ubbens H, Münzel T, Daiber A, Daub S. Role of CD40(L)-TRAF signaling in inflammation and resolution-a double-edged sword. Front Pharmacol 2022; 13:995061. [PMID: 36267276 PMCID: PMC9577411 DOI: 10.3389/fphar.2022.995061] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/12/2022] [Indexed: 11/26/2022] Open
Abstract
Cardiovascular diseases (CVD) and cardiovascular risk factors are the leading cause of death in the world today. According to the Global Burden of Disease Study, hypertension together with ischemic heart and cerebrovascular diseases is responsible for approximately 40% of all deaths worldwide. The major pathomechanism underlying almost all CVD is atherosclerosis, an inflammatory disorder of the vascular system. Recent large-scale clinical trials demonstrated that inflammation itself is an independent cardiovascular risk factor. Specific anti-inflammatory therapy could decrease cardiovascular mortality in patients with atherosclerosis (increased markers of inflammation). Inflammation, however, can also be beneficial by conferring so-called resolution, a process that contributes to clearing damaged tissue from cell debris upon cell death and thereby represents an essential step for recovery from, e.g., ischemia/reperfusion damage. Based on these considerations, the present review highlights features of the detrimental inflammatory reactions as well as of the beneficial process of immune cell-triggered resolution. In this context, we discuss the polarization of macrophages to either M1 or M2 phenotype and critically assess the role of the CD40L-CD40-TRAF signaling cascade in atherosclerosis and its potential link to resolution. As CD40L can bind to different cellular receptors, it can initiate a broad range of inflammatory processes that may be detrimental or beneficial. Likewise, the signaling of CD40L downstream of CD40 is mainly determined by activation of TRAF1-6 pathways that again can be detrimental or beneficial. Accordingly, CD40(L)-based therapies may be Janus-faced and require sophisticated fine-tuning in order to promote cardioprotection.
Collapse
Affiliation(s)
- Lea Strohm
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Henning Ubbens
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Steffen Daub
- Department of Cardiology, Cardiology I—Laboratory of Molecular Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| |
Collapse
|
18
|
CD40-CD40L in Neurological Disease. Int J Mol Sci 2022; 23:ijms23084115. [PMID: 35456932 PMCID: PMC9031401 DOI: 10.3390/ijms23084115] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Immune-inflammatory conditions in the central nervous system (CNS) rely on molecular and cellular interactions which are homeostatically maintained to protect neural tissue from harm. The CD40–CD40L interaction upregulates key proinflammatory molecules, a function best understood in the context of infection, during which B-cells are activated via CD40 signaling to produce antibodies. However, the role of CD40 in neurological disease of non-infectious etiology is unclear. We review the role of CD40–CD40L in traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis, ALS, myasthenia gravis and brain tumors. We also highlight therapeutic advancements targeting the CD40 system to either attenuate the neuroinflammatory response or leverage the downstream effects of CD40 signaling for direct tumor cell lysis.
Collapse
|
19
|
Mou L, Shi G, Cooper DK, Lu Y, Chen J, Zhu S, Deng J, Huang Y, Ni Y, Zhan Y, Cai Z, Pu Z. Current Topics of Relevance to the Xenotransplantation of Free Pig Islets. Front Immunol 2022; 13:854883. [PMID: 35432379 PMCID: PMC9010617 DOI: 10.3389/fimmu.2022.854883] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Pig islet xenotransplantation is a potential treatment for patients with type 1 diabetes. Current efforts are focused on identifying the optimal pig islet source and overcoming the immunological barrier. The optimal age of the pig donors remains controversial since both adult and neonatal pig islets have advantages. Isolation of adult islets using GMP grade collagenase has significantly improved the quantity and quality of adult islets, but neonatal islets can be isolated at a much lower cost. Certain culture media and coculture with mesenchymal stromal cells facilitate neonatal islet maturation and function. Genetic modification in pigs affords a promising strategy to prevent rejection. Deletion of expression of the three known carbohydrate xenoantigens (Gal, Neu5Gc, Sda) will certainly be beneficial in pig organ transplantation in humans, but this is not yet proven in islet transplantation, though the challenge of the '4th xenoantigen' may prove problematic in nonhuman primate models. Blockade of the CD40/CD154 costimulation pathway leads to long-term islet graft survival (of up to 965 days). Anti-CD40mAbs have already been applied in phase II clinical trials of islet allotransplantation. Fc region-modified anti-CD154mAbs successfully prevent the thrombotic complications reported previously. In this review, we discuss (I) the optimal age of the islet-source pig, (ii) progress in genetic modification of pigs, (iii) the immunosuppressive regimen for pig islet xenotransplantation, and (iv) the reduction in the instant blood-mediated inflammatory reaction.
Collapse
Affiliation(s)
- Lisha Mou
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Guanghan Shi
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
- Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada
| | - David K.C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States
| | - Ying Lu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jiao Chen
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Shufang Zhu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jing Deng
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yuanyuan Huang
- Department of Life Science, Bellevue College, Bellevue, WA, United States
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Yongqiang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Institute of Translational Medicine, Health Science Center, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Zuhui Pu
- Imaging Department, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, China
| |
Collapse
|
20
|
Salvadori M, Tsalouchos A. Innovative immunosuppression in kidney transplantation: A challenge for unmet needs. World J Transplant 2022; 12:27-41. [PMID: 35433332 PMCID: PMC8968476 DOI: 10.5500/wjt.v12.i3.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/27/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata Hospital, Florence 50012, Italy
| |
Collapse
|
21
|
Louis K, Macedo C, Metes D. Targeting T Follicular Helper Cells to Control Humoral Allogeneic Immunity. Transplantation 2021; 105:e168-e180. [PMID: 33909968 PMCID: PMC8484368 DOI: 10.1097/tp.0000000000003776] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ allografts after transplantation. Although the importance of T follicular helper (TFH) cells in controlling antibody responses has been long established, their role in directing donor-specific antibody generation leading to AMR was only recently appreciated in the clinical setting of organ transplantation. In this review, we provide a comprehensive summary of the current knowledge on the biology of human TFH cells as well as their circulating counterparts and describe their pivotal role in driving humoral alloimmunity. In addition, we discuss the intrinsic effects of current induction therapies and maintenance immunosuppressive drugs as well as of biotherapies on TFH cells and provide future directions and novel opportunities of biotherapeutic targeting of TFH cells that have the potential of bringing the prophylactic and curative treatments of AMR toward personalized and precision medicine.
Collapse
Affiliation(s)
- Kevin Louis
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Human Immunology and Immunopathology, Inserm UMR 976, Université de Paris, Paris, France
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Camila Macedo
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Diana Metes
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
22
|
Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
Collapse
Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| |
Collapse
|
23
|
Liu S, Xu J, Wu J. The Role of Co-Signaling Molecules in Psoriasis and Their Implications for Targeted Treatment. Front Pharmacol 2021; 12:717042. [PMID: 34354596 PMCID: PMC8329336 DOI: 10.3389/fphar.2021.717042] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/08/2021] [Indexed: 12/19/2022] Open
Abstract
Psoriasis is a chronic, systemic immune-mediated inflammatory disease manifesting in the skin, joint or both. Co-signaling molecules are essential for determining the magnitude of the T cell response to the antigen. According to the function of co-signaling molecules, they can be divided into co-stimulatory molecules and co-inhibitory molecules. The role of co-signaling molecules in psoriasis is recognized, mainly including the co-stimulatory molecules CD28, CD40, OX40, CD27, DR3, LFA-1, and LFA-3 and the co-inhibitory molecules CTLA-4, PD-1, and TIM-3. They impact the pathological process of psoriasis by modulating the immune strength of T cells, regulating the production of cytokines or the differentiation of Tregs. In recent years, immunotherapies targeting co-signaling molecules have made significant progress and shown broad application prospects in psoriasis. This review aims to outline the possible role of co-signaling molecules in the pathogenesis of psoriasis and their potential application for the treatment of psoriasis.
Collapse
Affiliation(s)
| | - Jinhua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinfeng Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
24
|
Russell AL, Prince C, Lundgren TS, Knight KA, Denning G, Alexander JS, Zoine JT, Spencer HT, Chandrakasan S, Doering CB. Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII. Mol Ther Methods Clin Dev 2021; 21:710-727. [PMID: 34141826 PMCID: PMC8181577 DOI: 10.1016/j.omtm.2021.04.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/29/2021] [Indexed: 01/09/2023]
Abstract
Hematopoietic stem and progenitor cell (HSPC) lentiviral gene therapy is a promising strategy toward a lifelong cure for hemophilia A (HA). The primary risks associated with this approach center on the requirement for pre-transplantation conditioning necessary to make space for, and provide immune suppression against, stem cells and blood coagulation factor VIII, respectively. Traditional conditioning agents utilize genotoxic mechanisms of action, such as DNA alkylation, that increase risk of sterility, infection, and developing secondary malignancies. In the current study, we describe a non-genotoxic conditioning protocol using an immunotoxin targeting CD117 (c-kit) to achieve endogenous hematopoietic stem cell depletion and a cocktail of monoclonal antibodies to provide transient immune suppression against the transgene product in a murine HA gene therapy model. This strategy provides high-level engraftment of hematopoietic stem cells genetically modified ex vivo using recombinant lentiviral vector (LV) encoding a bioengineered high-expression factor VIII variant, termed ET3. Factor VIII procoagulant activity levels were durably elevated into the normal range and phenotypic correction achieved. Furthermore, no immunological rejection or development of anti-ET3 immunity was observed. These preclinical data support clinical translation of non-genotoxic antibody-based conditioning in HSPC LV gene therapy for HA.
Collapse
Affiliation(s)
- Athena L. Russell
- Graduate Program in Genetics and Molecular Biology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - Chengyu Prince
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Taran S. Lundgren
- Graduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - Kristopher A. Knight
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Graduate Program in Molecular and Systems Pharmacology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | | | - Jordan S. Alexander
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jaquelyn T. Zoine
- Graduate Program in Cancer Biology, Laney Graduate School, Emory University, Atlanta, GA 30322, USA
| | - H. Trent Spencer
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Expression Therapeutics, LLC, Tucker, GA 30084, USA
| | - Shanmuganathan Chandrakasan
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Christopher B. Doering
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Expression Therapeutics, LLC, Tucker, GA 30084, USA
| |
Collapse
|
25
|
CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. J Clin Med 2020; 9:jcm9113653. [PMID: 33202988 PMCID: PMC7697100 DOI: 10.3390/jcm9113653] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/06/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
The cluster of differentiation 40 (CD40) is activated by the CD40 ligand (CD40L) in a variety of diverse cells types and regulates important processes associated with kidney disease. The CD40/CD40L signaling cascade has been comprehensively studied for its roles in immune functions, whereas the signaling axis involved in local kidney injury has only drawn attention in recent years. Clinical studies have revealed that circulating levels of soluble CD40L (sCD40L) are associated with renal function in the setting of kidney disease. Levels of the circulating CD40 receptor (sCD40), sCD40L, and local CD40 expression are tightly related to renal injury in different types of kidney disease. Additionally, various kidney cell types have been identified as non-professional antigen-presenting cells (APCs) that express CD40 on the cell membrane, which contributes to the interactions between immune cells and local kidney cells during the development of kidney injury. Although the potential for adverse CD40 signaling in kidney cells has been reported in several studies, a summary of those studies focusing on the role of CD40 signaling in the development of kidney disease is lacking. In this review, we describe the outcomes of recent studies and summarize the potential therapeutic methods for kidney disease which target CD40.
Collapse
|
26
|
Tang T, Cheng X, Truong B, Sun L, Yang X, Wang H. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint. Pharmacol Ther 2020; 219:107709. [PMID: 33091428 DOI: 10.1016/j.pharmthera.2020.107709] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/15/2020] [Indexed: 12/22/2022]
Abstract
The CD40 receptor and its ligand CD40L is one of the most critical molecular pairs of the stimulatory immune checkpoints. Both CD40 and CD40L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induce CD40 trimerization and downstream signaling. The canonical CD40/CD40L signaling is mediated by recruitment of TRAFs and NF-κB activation, which is supplemented by signal pathways such as PI3K/AKT, MAPKs and JAK3/STATs. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. Because of its essential role in immune activation, CD40/CD40L interaction has been regarded as an attractive immunotherapy target. In recent years, significant advance has been made in CD40/CD40L-targeted therapy. Various types of agents, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors and protein antagonist, have been developed and evaluated in early-stage clinical trials for treating malignancies, autoimmune diseases and allograft rejection. In general, these agents have demonstrated favorable safety and some of them show promising clinical efficacy. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection. This review provides a comprehensive overview of the structure, processing, cellular expression pattern, signaling and effector function of CD40/CD40L checkpoint molecules. In addition, we summarize the progress, targeted diseases and outcomes of current ongoing and completed clinical trials of CD40/CD40L-targeted therapy.
Collapse
Affiliation(s)
- TingTing Tang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Billy Truong
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - LiZhe Sun
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Cardiovascular Medicine, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - XiaoFeng Yang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
| |
Collapse
|
27
|
Abstract
Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.
Collapse
|
28
|
Park JB. Future direction of immunosuppressive treatment in organ transplantation. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2020. [DOI: 10.5124/jkma.2020.63.5.259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Since the first success of kidney transplantation in 1954, significant advances have been achieved in the field of organ transplantation. It was possible with the introduction of immunosuppressive drugs belonging to the class of calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus, the advances in surgical techniques and perioperative management, the monitoring and management infections, and the highly sensitive and specific antibody detection techniques. Despite recent progress, we currently encounter the limitation of better long-term transplant outcomes mainly because of paradoxical CNI toxicity and failure to control antibody or antibody-mediated rejections. The future direction of immunosuppression can be continued by optimizing immunosuppressive regimens with currently available immunosuppressants for better control of antibodies while avoiding CNI toxicity and by using biological therapeutics such as costimulation blockade agents that provide effective control of antibodies along with a reduction in usage or avoidance of CNIs and may develop as new immunosuppressants in the near future. Moreover, a tolerance induction through transplantation of donor hematopoietic stem cells or an infusion of regulatory cells using various sources of immune cells can also be a promising strategy as it can fundamentally escape from the complications of immunosuppressants. Over and above, it is important to note that the results of clinically applicable immunosuppressants from research in the non-human primate xenotransplantation model at the forefront of the future development of immunosuppressants can be a good opportunity to selectively apply to allo-transplants. No immunosuppressants can be risk-free, and therefore, all new immunosuppressants should be evaluated under the considerations for the risk/benefit ratio in various clinical conditions.
Collapse
|
29
|
Vincenti F, Klintmalm G, Yang H, Ram Peddi V, Blahunka P, Conkle A, Santos V, Holman J. A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation. Am J Transplant 2020; 20:172-180. [PMID: 31397943 PMCID: PMC6972670 DOI: 10.1111/ajt.15560] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 07/27/2019] [Accepted: 07/28/2019] [Indexed: 01/25/2023]
Abstract
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUCinf , Cmax , and AUClast . The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUCinf and AUClast demonstrated a more than dose-proportional increase in the range of 50-500 mg, and Cmax increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment-emergent anti-bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose-dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).
Collapse
Affiliation(s)
- Flavio Vincenti
- Department of Medicine and SurgeryUniversity of California San FranciscoSan FranciscoCalifornia
| | - Goran Klintmalm
- Department of Transplantation ServicesAnnette C. and Harold C. Simmons Transplant InstituteDallasTexas
| | - Harold Yang
- Department of SurgeryPinnacle Health Transplant AssociatesHarrisburgPennsylvania
| | - V. Ram Peddi
- Department of TransplantationCalifornia Pacific Medical CenterSan FranciscoCalifornia
| | - Paul Blahunka
- Astellas Pharma Global Development, Inc.NorthbrookIllinois
| | - Angela Conkle
- Astellas Pharma Global Development, Inc.NorthbrookIllinois
| | - Vicki Santos
- Astellas Pharma Global Development, Inc.NorthbrookIllinois
| | - John Holman
- Astellas Pharma Global Development, Inc.NorthbrookIllinois
| |
Collapse
|