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Low HY, Yang CT, Xia B, He T, Lam WWC, Ng DCE. Radiolabeled Liposomes for Nuclear Imaging Probes. Molecules 2023; 28:molecules28093798. [PMID: 37175207 PMCID: PMC10180453 DOI: 10.3390/molecules28093798] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/17/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Quantitative nuclear imaging techniques are in high demand for various disease diagnostics and cancer theranostics. The non-invasive imaging modality requires radiotracing through the radioactive decay emission of the radionuclide. Current preclinical and clinical radiotracers, so-called nuclear imaging probes, are radioisotope-labeled small molecules. Liposomal radiotracers have been rapidly developing as novel nuclear imaging probes. The physicochemical properties and structural characteristics of liposomes have been elucidated to address their long circulation and stability as radiopharmaceuticals. Various radiolabeling methods for synthesizing radionuclides onto liposomes and synthesis strategies have been summarized to render them biocompatible and enable specific targeting. Through a variety of radionuclide labeling methods, radiolabeled liposomes for use as nuclear imaging probes can be obtained for in vivo biodistribution and specific targeting studies. The advantages of radiolabeled liposomes including their use as potential clinical nuclear imaging probes have been highlighted. This review is a comprehensive overview of all recently published liposomal SPECT and PET imaging probes.
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Affiliation(s)
- Ho Ying Low
- Department of Nuclear Medicine and Molecular Imaging, Radiological Sciences Division, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
| | - Chang-Tong Yang
- Department of Nuclear Medicine and Molecular Imaging, Radiological Sciences Division, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Bin Xia
- School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, China
| | - Tao He
- School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, China
| | - Winnie Wing Chuen Lam
- Department of Nuclear Medicine and Molecular Imaging, Radiological Sciences Division, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - David Chee Eng Ng
- Department of Nuclear Medicine and Molecular Imaging, Radiological Sciences Division, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
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Kauffman N, Morrison J, O’Brien K, Fan J, Zinn KR. Intra-Arterial Delivery of Radiopharmaceuticals in Oncology: Current Trends and the Future of Alpha-Particle Therapeutics. Pharmaceutics 2023; 15:pharmaceutics15041138. [PMID: 37111624 PMCID: PMC10144492 DOI: 10.3390/pharmaceutics15041138] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
A paradigm shift is underway in cancer diagnosis and therapy using radioactivity-based agents called radiopharmaceuticals. In the new strategy, diagnostic imaging measures the tumor uptake of radioactive agent “X” in a patient’s specific cancer, and if uptake metrics are realized, the patient can be selected for therapy with radioactive agent “Y”. The X and Y represent different radioisotopes that are optimized for each application. X–Y pairs are known as radiotheranostics, with the currently approved route of therapy being intravenous administration. The field is now evaluating the potential of intra-arterial dosing of radiotheranostics. In this manner, a higher initial concentration can be achieved at the cancer site, which could potentially enhance tumor-to-background targeting and lead to improved imaging and therapy. Numerous clinical trials are underway to evaluate these new therapeutic approaches that can be performed via interventional radiology. Of further interest is changing the therapeutic radioisotope that provides radiation therapy by β- emission to radioisotopes that also decay by α-particle emissions. Alpha (α)-particle emissions provide high energy transfer to the tumors and have distinct advantages. This review discusses the current landscape of intra-arterially delivered radiopharmaceuticals and the future of α-particle therapy with short-lived radioisotopes.
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Affiliation(s)
- Nathan Kauffman
- Comparative Medicine and Integrative Biology, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - James Morrison
- Advanced Radiology Services, 3264 N Evergreen Dr, Grand Rapids, MI 49525, USA
| | - Kevin O’Brien
- Department of Radiology, Henry Ford Health System, Detroit, MI 48202, USA
| | - Jinda Fan
- Departments of Radiology and Chemistry, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Kurt R. Zinn
- Departments of Radiology, Biomedical Engineering, Small Animal Clinical Sciences, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, USA
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Si Z, Cheng Y, Xu Z, Shi D, Shi H, Cheng D. Exploration of 68Ga-DOTA-MAL as a Versatile Vehicle for Facile Labeling of a Variety of Thiol-Containing Bioactive Molecules. ACS OMEGA 2023; 8:4747-4755. [PMID: 36777559 PMCID: PMC9909812 DOI: 10.1021/acsomega.2c06720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/19/2023] [Indexed: 06/18/2023]
Abstract
Efficient and site-specific radiolabeling reactions are essential in molecular probe synthesis. Thus, selecting an effective method for radiolabeling that does not affect bioactivity of the molecule is critical. Varieties of bifunctional chelating agents provide a solution in this matter. As a chemo-specific chelator, maleimido-mono-amide-DOTA (DOTA-Mal) holds significant potential for 68Ga labeling of bioactive molecules; it can react specifically with free sulfhydryl groups under mild conditions. Compared with amino and carboxylic acid groups, free sulfhydryl groups are relatively less common in most biomolecules and can serve as site-specific radiolabeling targets. Labeling of 68Ga usually employs a two-step labeling strategy; first, chelators are conjugated to the biomolecules, which is followed by radiolabeling. However, the bioactivity of biomolecules may be affected by harsh labeling conditions. In this study, three 68Ga-labeled bioactive molecules, namely, 68Ga-DOTA-RGD, 68Ga-DOTA-FA, and 68Ga-DOTA-BSA, were prepared using a novel strategy under mild conditions (pH of 8.0 at room temperature). Using this strategy, DOTA-Mal was labeled by 68Ga before it reacted with the sulfhydryl group-containing biomolecules, which avoided damage to said biomolecules caused by the harsh reaction conditions required in 68Ga-labeling procedures. The biological and chemical properties of these three radiotracers synthesized using this strategy are well manifested. Through a series of experiments, the effectiveness of this strategy is demonstrated, and we believe that this site-specific bioactivity-friendly reaction strategy will facilitate developments and translation applications of varieties of 68Ga-labeled positron emission tomography probes.
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Affiliation(s)
- Zhan Si
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
| | - Yuan Cheng
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
| | - Zhan Xu
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
| | - Dai Shi
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
| | - Hongcheng Shi
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
| | - Dengfeng Cheng
- Department
of Nuclear Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai 200032, China
- Shanghai
Institute of Medical Imaging, Shanghai 200032, China
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Pastorino S, Baldassari S, Ailuno G, Zuccari G, Drava G, Petretto A, Cossu V, Marini C, Alfei S, Florio T, Sambuceti G, Caviglioli G. Two Novel PET Radiopharmaceuticals for Endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1) Targeting. Pharmaceutics 2021; 13:1025. [PMID: 34371717 PMCID: PMC8309178 DOI: 10.3390/pharmaceutics13071025] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 01/17/2023] Open
Abstract
Atherosclerosis is a chronic progressive disease involving inflammatory events, such as the overexpression of adhesion molecules including the endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1). VCAM-1 is rapidly overexpressed in the first stages of atherosclerosis, thus representing a promising target for early atheroma detection. Two novel Positron Emission Tomography (PET) radiopharmaceuticals (MacroP and NAMP), based on the VCAM-1-binding peptide having sequence VHPKQHRGGSKGC, were synthesized and characterized. MacroP is derived from the direct conjugation of a DOTA derivative with the peptide, while NAMP is a biotin derivative conceived to be employed in a three-step pretargeting system, involving the use of a double-chelating derivative of DOTA. The identity of the newly synthesized radiopharmaceuticals was confirmed by mass spectrometry and, after radiolabeling with 68Ga, both showed high radiochemical purity; in vitro tests on human umbilical vein endothelial cells evidenced their VCAM-1 binding ability, with higher radioactive uptake in the case of NAMP. Moreover, NAMP might also be employed in a theranostic approach in association with functionalized biotinylated nanoparticles.
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Affiliation(s)
- Sara Pastorino
- Nuclear Medicine Unit, S. Andrea Hospital, via Vittorio Veneto 197, 19124 La Spezia, Italy;
| | - Sara Baldassari
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
| | - Giorgia Ailuno
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
| | - Guendalina Zuccari
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
| | - Giuliana Drava
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
| | - Andrea Petretto
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genova, Italy;
| | - Vanessa Cossu
- Department of Health Science, University of Genova—Nuclear Medicine Unit, via A. Pastore 1, 16132 Genova, Italy; (V.C.); (C.M.); (G.S.)
- IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy;
| | - Cecilia Marini
- Department of Health Science, University of Genova—Nuclear Medicine Unit, via A. Pastore 1, 16132 Genova, Italy; (V.C.); (C.M.); (G.S.)
- IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy;
- CNR Institute of Bioimages and Molecular Physiology, via Fratelli Cervi 93, 20090 Segrate, Italy
| | - Silvana Alfei
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
| | - Tullio Florio
- IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy;
- Department of Internal Medicine, University of Genova, viale Benedetto XV 2, 16136 Genova, Italy
| | - Gianmario Sambuceti
- Department of Health Science, University of Genova—Nuclear Medicine Unit, via A. Pastore 1, 16132 Genova, Italy; (V.C.); (C.M.); (G.S.)
- IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, 16132 Genova, Italy;
| | - Gabriele Caviglioli
- Department of Pharmacy, University of Genova, viale Cembrano 4, 16148 Genova, Italy; (S.B.); (G.A.); (G.Z.); (G.D.); (S.A.)
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Abstract
Immuno-positron emission tomography (immunoPET) is a paradigm-shifting molecular imaging modality combining the superior targeting specificity of monoclonal antibody (mAb) and the inherent sensitivity of PET technique. A variety of radionuclides and mAbs have been exploited to develop immunoPET probes, which has been driven by the development and optimization of radiochemistry and conjugation strategies. In addition, tumor-targeting vectors with a short circulation time (e.g., Nanobody) or with an enhanced binding affinity (e.g., bispecific antibody) are being used to design novel immunoPET probes. Accordingly, several immunoPET probes, such as 89Zr-Df-pertuzumab and 89Zr-atezolizumab, have been successfully translated for clinical use. By noninvasively and dynamically revealing the expression of heterogeneous tumor antigens, immunoPET imaging is gradually changing the theranostic landscape of several types of malignancies. ImmunoPET is the method of choice for imaging specific tumor markers, immune cells, immune checkpoints, and inflammatory processes. Furthermore, the integration of immunoPET imaging in antibody drug development is of substantial significance because it provides pivotal information regarding antibody targeting abilities and distribution profiles. Herein, we present the latest immunoPET imaging strategies and their preclinical and clinical applications. We also emphasize current conjugation strategies that can be leveraged to develop next-generation immunoPET probes. Lastly, we discuss practical considerations to tune the development and translation of immunoPET imaging strategies.
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Affiliation(s)
- Weijun Wei
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, 1111 Highland Avenue, Room 7137, Madison, Wisconsin 53705, United States
| | - Zachary T Rosenkrans
- Department of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Jianjun Liu
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Gang Huang
- Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
| | - Quan-Yong Luo
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, 1111 Highland Avenue, Room 7137, Madison, Wisconsin 53705, United States
- Department of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
- University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53705, United States
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Eskian M, Khorasanizadeh M, Zinzani PL, Illidge TM, Rezaei N. Novel Methods to Improve the Efficiency of Radioimmunotherapy for Non-Hodgkin Lymphoma. Int Rev Immunol 2019; 38:79-91. [PMID: 30931651 DOI: 10.1080/08830185.2019.1588266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Radioimmunotherapy (RIT) is a novel strategy for treating non-Hodgkin lymphoma (NHL). Several studies have shown the promising results of using RIT in NHL, which have led to FDA approval for two RIT agents in treating low grade NHL. In spite of these favorable results in low-grade NHL, most of the aggressive or relapsed/refractory NHL subjects experience relapses following RIT. Although more aggressive treatments such as myeloablative doses of RIT followed by stem cell transplantation appear to be able to provide a longer survival for some patients these approaches are associated with significant treatment-related adverse events and challenging to deliver in most centers. Therefore, it seems reasonable to develop treatment approaches that enhance the efficiency of RIT, while reducing its toxicity. In this paper, novel methods that improve the efficiency of RIT and reduce its toxicity through various mechanisms are reviewed. Further clinical development of these methods could expand the NHL patient groups eligible for receiving RIT, and even extend the use of RIT to new indications and disease groups in future.
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Affiliation(s)
- Mahsa Eskian
- a Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran , Iran.,b Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - MirHojjat Khorasanizadeh
- a Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran , Iran.,b Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
| | - Pier Luigi Zinzani
- c Institute of Hematology "L. e A. Seràgnoli", University of Bologna , Bologna , Italy
| | - Tim M Illidge
- d Manchester Academic Health Sciences Centre, University of Manchester, Christie NHS Foundation Trust , Manchester , UK
| | - Nima Rezaei
- a Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences , Tehran , Iran.,e Department of Immunology, School of Medicine , Tehran University of Medical Sciences , Tehran , Iran.,f Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN) , Tehran , Iran
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Patra M, Zarschler K, Pietzsch HJ, Stephan H, Gasser G. New insights into the pretargeting approach to image and treat tumours. Chem Soc Rev 2018; 45:6415-6431. [PMID: 27722526 DOI: 10.1039/c5cs00784d] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Tumour pretargeting is a promising strategy for cancer diagnosis and therapy allowing for the rational use of long circulating, highly specific monoclonal antibodies (mAbs) for both non-invasive cancer radioimmunodetection (RID) and radioimmunotherapy (RIT). In contrast to conventional RID/RIT where the radionuclides and oncotropic vector molecules are delivered as presynthesised radioimmunoconjugates, the pretargeting approach is a multistep procedure that temporarily separates targeting of certain tumour-associated antigens from delivery of diagnostic or therapeutic radionuclides. In principle, unlabelled, highly tumour antigen specific mAb conjugates are, in a first step, administered into a patient. After injection, sufficient time is allowed for blood circulation, accumulation at the tumour site and subsequent elimination of excess mAb conjugates from the body. The small fast-clearing radiolabelled effector molecules with a complementary functionality directed to the prelocalised mAb conjugates are then administered in a second step. Due to its fast pharmacokinetics, the small effector molecules reach the malignant tissue quickly and bind the local mAb conjugates. Thereby, corresponding radioimmunoconjugates are formed in vivo and, consequently, radiation doses are deposited mainly locally. This procedure results in a much higher tumour/non-tumour (T/NT) ratio and is favourable for cancer diagnosis and therapy as it substantially minimises the radiation damage to non-tumour cells of healthy tissues. The pretargeting approach utilises specific non-covalent interactions (e.g. strept(avidin)/biotin) or covalent bond formations (e.g. inverse electron demand Diels-Alder reaction) between the tumour bound antibody and radiolabelled small molecules. This tutorial review descriptively presents this complex strategy, addresses the historical as well as recent preclinical and clinical advances and discusses the advantages and disadvantages of different available variations.
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Affiliation(s)
- Malay Patra
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
| | - Kristof Zarschler
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, Germany.
| | - Hans-Jürgen Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, Germany.
| | - Holger Stephan
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, D-01328 Dresden, Germany.
| | - Gilles Gasser
- Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Frampas E, Faivre-Chauvet A, Rauscher A, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J. A pretargeting system for tumor PET imaging and radioimmunotherapy. Front Pharmacol 2015; 6:54. [PMID: 25873896 PMCID: PMC4379897 DOI: 10.3389/fphar.2015.00054] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 03/04/2015] [Indexed: 11/21/2022] Open
Abstract
Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.
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Affiliation(s)
- Françoise Kraeber-Bodéré
- Nuclear Medicine Department, Nantes University Hospital Nantes, France ; Nuclear Medicine Department, Institut de Cancérologie de l'Ouest René Gauducheau Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France
| | - Caroline Rousseau
- Nuclear Medicine Department, Institut de Cancérologie de l'Ouest René Gauducheau Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France
| | - Caroline Bodet-Milin
- Nuclear Medicine Department, Nantes University Hospital Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France
| | - Eric Frampas
- Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France ; Radiology Department, Nantes University Hospital Nantes, France
| | - Alain Faivre-Chauvet
- Nuclear Medicine Department, Nantes University Hospital Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France
| | - Aurore Rauscher
- Nuclear Medicine Department, Institut de Cancérologie de l'Ouest René Gauducheau Nantes, France ; Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France
| | | | - David M Goldenberg
- Immunomedics, Inc. Morris Plains, NJ, USA ; Garden State Cancer Center, Center for Molecular Medicine and Immunology Morris Plains, NJ, USA
| | | | - Jacques Barbet
- Cancer Research Center, University of Nantes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique Nantes, France ; GIP Arronax Saint-Herblain, France
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9
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Knight JC, Mosley M, Stratford MRL, Uyeda HT, Benink HA, Cong M, Fan F, Faulkner S, Cornelissen B. Development of an enzymatic pretargeting strategy for dual-modality imaging. Chem Commun (Camb) 2015; 51:4055-8. [PMID: 25660394 DOI: 10.1039/c4cc10265g] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2024]
Abstract
A pretargeted imaging strategy based on the HaloTag dehalogenase enzyme is described. Here, a HaloTag-Trastuzumab conjugate has been used as the primary agent targeting HER2 expression, and three new radiolabelled HaloTag ligands have been used as secondary agents, two of which offer dual-modality (SPECT/optical) imaging capability.
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Affiliation(s)
- J C Knight
- CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
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10
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Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. ScientificWorldJournal 2014; 2014:492061. [PMID: 25379535 PMCID: PMC4213411 DOI: 10.1155/2014/492061] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 08/04/2014] [Indexed: 12/23/2022] Open
Abstract
Radioimmunotherapy (RIT) represents a selective internal radiation therapy, that is, the use of radionuclides conjugated to tumor-directed monoclonal antibodies (including those fragments) or peptides. In a clinical field, two successful examples of this treatment protocol are currently extended by 90Y-ibritumomab tiuxetan (Zevalin) and 131I-tositumomab (Bexxar), both of which are anti-CD20 monoclonal antibodies coupled to cytotoxic radioisotopes and are approved for the treatment of non-Hodgkin lymphoma patients. In addition, some beneficial observations are obtained in preclinical studies targeting solid tumors. To date, in order to reduce the unnecessary exposure and to enhance the therapeutic efficacy, various biological, chemical, and treatment procedural improvements have been investigated in RIT. This review outlines the fundamentals of RIT and current knowledge of the preclinical/clinical trials for cancer treatment.
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An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications. World J Methodol 2013; 3:45-64. [PMID: 25237623 PMCID: PMC4145570 DOI: 10.5662/wjm.v3.i4.45] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 10/03/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin (123I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid 123I-Hyp and the commercially available 99mTc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce costs and save resources. However, cross-contaminations with blood-borne pathogens of infectious diseases may occur. We developed a radioactive method for safety evaluation of a new replaceable patient-delivery system. By mimicking pathogens with a radiotracer, we assessed the feasibility of using the system repeatedly without septic risks. This overview is deemed to be interesting to those involved in the related fields for translational research.
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Abstract
Targeting of radionuclides with antibodies, or radioimmunotherapy, has been an active field of research spanning nearly 50 years, evolving with advancing technologies in molecular biology and chemistry, and with many important preclinical and clinical studies illustrating the benefits, but also the challenges, which all forms of targeted therapies face. There are currently two radiolabeled antibodies approved for the treatment of non-Hodgkin lymphoma, but radioimmunotherapy of solid tumors remains a challenge. Novel antibody constructs, focusing on treatment of localized and minimal disease, and pretargeting are all promising new approaches that are currently under investigation.
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Morpurgo M, Facchin S, Pignatto M, Silvestri D, Casarin E, Realdon N. Characterization of multifunctional nanosystems based on the avidin-nucleic acid interaction as signal enhancers in immuno-detection. Anal Chem 2012; 84:3433-9. [PMID: 22414051 DOI: 10.1021/ac300276u] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The Avidin-Nucleic-Acids-Nano-Assembly (ANANAS) is a kind of soft poly avidin nanoparticle originating from the high affinity interaction between avidin and the nucleic acids. In this work we investigated the possibility of transforming ANANAS cores into stoichiometrically controlled multifunctional nanoparticles through a "one-pot" procedure, and we measured in a quantitative way their ability to work as reagents for enhanced immunodiagnostic detection. Initially, we measured the ANANAS loading capability for biotinylated proteins of different nature. About 200 molecules of biotin-horseradish-peroxidase (40KDa b-HRP) and 60 molecules of biotin-immunoglobulin-G (150KDa b-IgG) could be accommodated onto each nanoparticle, showing that steric limitations dictate the number of loadable entities. Stoichiometrically controlled functional assemblies were generated by mixing core particles with subsaturating amounts of b-HRP and b-IgG. When applied as detection reagents in an Enzyme-Linked-ImmunoSorbed-Assay (ELISA), these assemblies were up to two-orders of magnitude more sensitive than commercial HRP-based reagents. Assemblies of different composition displayed different efficacy, indicating that the system functionality can be fine-tuned. Within-assay variability (CV%), measured to assess if the assembly procedure is reproducible, was within 10%. Stability experiments demonstrated that the functionalyzed assemblies are stable in solution for more than one week. In principle, any biotinylated function can be loaded onto the core particle, whose high loading capacity and tunability may open the way toward further application in biomedicine.
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Affiliation(s)
- Margherita Morpurgo
- Pharmaceutical Chemistry and Pharmacology Department, The University of Padova, Via Marzolo, 5, 35131 Padova.
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Cona MM, Wang H, Li J, Feng Y, Chen F, de Witte P, Verbruggen A, Ni Y. Continuing pursuit for ideal systemic anticancer radiotherapeutics. Invest New Drugs 2011; 30:2050-65. [PMID: 22006160 DOI: 10.1007/s10637-011-9758-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2011] [Accepted: 10/04/2011] [Indexed: 12/22/2022]
Abstract
Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted radiotherapy (STR) is a radiotherapeutic modality based on systemic administration of radioactive agents for selectively delivering high doses of energy to destroy cancer cells. For this purpose, diverse tumour-target specific agents including monoclonal antibodies (MoAb), MoAb fragments and peptides have been tested and some of them have already got FDA approval for clinical use. However, MoAbs and their tailored analogues have shown non-homogeneous tumour distribution, limited diffusion, insufficient intratumoral accumulation and retention, unwanted uptake in normal tissues and scarcity of identified cancer antigens for generating new MoAbs. Similarly, peptides have also exhibited retention in normal organs, lacks of favourable membrane permeability or drug cell internalization and short-term residence in cancer cells. Recently, a new category of target-specific agent with strong affinity for necrosis has emerged as an excellent option for developing targeted radiotherapeutic agents to be used after necrosis-inducing treatments (NITs). The combination of their high, specific and long-term accumulation and retention at necrotic sites with the crossfire effect of ionizing particle-emitters allows irradiating adjacent residual viable tumour cells during a prolonged period of time. It may considerably enhance the therapeutic response and open a new horizon for improved cancer treatability or curability.
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Affiliation(s)
- Marlein Miranda Cona
- Radiology Section, Department of Medical Diagnostic Sciences, Biomedical Sciences Group, University of Leuven, Leuven, Belgium
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Zurrida S, Veronesi U. A New TNM Classification for Breast Cancer to Meet the Demands of the Present and the Challenges of the Future. WOMENS HEALTH 2011; 7:41-9. [DOI: 10.2217/whe.10.82] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In this article we will describe our proposed changes to the breast cancer tumor node metastasis (TNM) classification which, while retaining TNM structure to ensure backwards compatibility, will render it more useful and better able to accommodate future developments. We propose changing T to specify exact tumor size (a tumor of pathological diameter 1.7 cm would be pT1.7); changing N to specify the number of metastatic lymph nodes over the total number removed (e.g., pN5/21); adding suffixes to M to indicate metastatic site; removing in situ neoplasms from the classification, since they are not carcinomas and are incapable of metastasizing; and removing the terms ‘infiltrating’ and ‘invasive’ since they are redundant. Finally, we would include hormone receptor, HER2, and other biological indicators of prognosis, as they are verified, in a placeholder system appended to the TNM. These proposals shift the emphasis from the quantity of tumor present to the quality of the cancer.
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Affiliation(s)
- Stefano Zurrida
- Senology Department, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milan, Italy
- University of Milan, School of Medicine, Via Festa del Perdono, 7, 20122 Milan, Italy
| | - Umberto Veronesi
- Scientific Director, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milan, Italy
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Walter RB, Press OW, Pagel JM. Pretargeted radioimmunotherapy for hematologic and other malignancies. Cancer Biother Radiopharm 2010; 25:125-42. [PMID: 20423225 DOI: 10.1089/cbr.2010.0759] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Radioimmunotherapy (RIT) has emerged as one of the most promising treatment options, particularly for hematologic malignancies. However, this approach has generally been limited by a suboptimal therapeutic index (target-to-nontarget ratio) and an inability to deliver sufficient radiation doses to tumors selectively. Pretargeted RIT (PRIT) circumvents these limitations by separating the targeting vehicle from the subsequently administered therapeutic radioisotope, which binds to the tumor-localized antibody or is quickly excreted if unbound. A growing number of preclinical proof-of-principle studies demonstrate that PRIT is feasible and safe and provides improved directed radionuclide delivery to malignant cells compared with conventional RIT while sparing normal cells from nonspecific radiotoxicity. Early phase clinical studies corroborate these preclinical findings and suggest better efficacy and lesser toxicities in patients with hematologic and other malignancies. With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities.
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Affiliation(s)
- Roland B Walter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
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Paganelli G, Ferrari M, Ravasi L, Cremonesi M, De Cicco C, Galimberti V, Sivolapenko G, Luini A, De Santis R, Travaini LL, Fiorenza M, Chinol M, Papi S, Zanna C, Carminati P, Veronesi U. Intraoperative avidination for radionuclide therapy: a prospective new development to accelerate radiotherapy in breast cancer. Clin Cancer Res 2007; 13:5646s-5651s. [PMID: 17875802 DOI: 10.1158/1078-0432.ccr-07-1058] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE In a continuous effort to seek for anticancer treatments with minimal side effects, we aim at proving the feasibility of the Intraoperative Avidination for Radionuclide Therapy, a new procedure for partial breast irradiation. EXPERIMENTAL DESIGN To assess doses of 90Y-DOTA-biotin to target (i.e., breast tumor bed) and nontarget organs, we did simulation studies with 111In-DOTA-biotin in 10 candidates for conservative breast surgery. Immediately after quadrantectomy, patients were injected with 100-mg avidin in the tumor bed. On the following day, patients were given 111In-DOTA-biotin (approximately 111 MBq) i.v. after appropriate chase of biotinylated albumin (20 mg) to remove circulating avidin. Biokinetic studies were done by measuring radioactivity in scheduled blood samples, 48-h urine collection, and through scintigraphic images. The medical internal radiation dose formalism (OLINDA code) enabled dosimetry assessment in target and nontarget organs. RESULTS Images showed early and long-lasting radioactive biotin uptake in the operated breast. Rapid blood clearance (<1% at 12 h) and urine excretion (>75% at 24 h) were observed. Absorbed doses, expressed as mean+/-SD in Gy/GBq, were as low as 0.15+/-0.05 in lungs, 0.10+/-0.02 in heart, 0.06+/-0.02 in red marrow, 1.30+/-0.50 in kidneys, 1.50+/-0.30 in urinary bladder, and 0.06+/-0.02 in total body, whereas in the targeted area, they increased to 5.5+/-1.1 Gy/GBq (50% ISOROI) and 4.8+/-1.0 Gy/GBq (30% ISOROI). CONCLUSION Our preliminary results suggest that Intraoperative Avidination for Radionuclide Therapy is a simple and feasible procedure that may improve breast cancer patients' postsurgical management by shortening radiotherapy duration.
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Affiliation(s)
- Giovanni Paganelli
- Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy.
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Mårtensson L, Nilsson R, Ohlsson T, Sjögren HO, Strand SE, Tennvall J. Improved Tumor Targeting and Decreased Normal Tissue Accumulation through Extracorporeal Affinity Adsorption in a Two-Step Pretargeting Strategy. Clin Cancer Res 2007; 13:5572s-5576s. [PMID: 17875791 DOI: 10.1158/1078-0432.ccr-07-0891] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Evaluation of the possibilities of reducing the accumulation of radiolabeled streptavidin in radiosensitive organs by extracorporeal affinity adsorption (ECAT). EXPERIMENTAL DESIGN Rats were injected with biotinylated antibody and subjected to removal of the antibodies from the circulation by ECAT 24 h after injection (avidin column). Animals were then injected with 111In-1,4,7,10-tetra-azacylododecane N,N',N'',N'''-tetraacetic acid (DOTA)-streptavidin. In a third step, animals were subjected to a second ECAT 8 h after injection to remove the DOTA-streptavidin from the circulation (biotin column). Biodistribution and tumor targeting of DOTA-streptavidin 24 h after injection was determined. RESULTS Elimination of biotinylated antibody by ECAT before injection of DOTA-streptavidin increased the tumor targeting by 50%. In addition, the levels of DOTA-streptavidin in liver and lymph nodes were reduced by 60%, which implied a 4.3- and 3.8-fold increase of tumor-to-liver and tumor-to-lymph node ratios, respectively. By doing a second ECAT to remove DOTA-streptavidin from the circulation, accumulation in normal tissues was reduced. However, this latter ECAT also reduced tumor accumulation by 25% (mostly corresponding to radioactivity in the circulation). CONCLUSIONS ECAT was efficient as a means of removing biotinylated antibodies and would probably also be efficient for the clearance of streptavidin-conjugated antibodies. Conversely, the use of ECAT for removal of radiolabeled streptavidin seems not to offer any advantage.
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Cai W, Niu G, Chen X. Multimodality imaging of the HER-kinase axis in cancer. Eur J Nucl Med Mol Imaging 2007; 35:186-208. [PMID: 17846765 DOI: 10.1007/s00259-007-0560-9] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2007] [Accepted: 07/20/2007] [Indexed: 12/23/2022]
Abstract
The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases controls critical pathways involved in epithelial cell differentiation, growth, division, and motility. Alterations and disruptions in the function of the HER-kinase axis can lead to malignancy. Many therapeutic agents targeting the HER-kinase axis are approved for clinical use or are in preclinical/clinical development. The ability to quantitatively image the HER-kinase axis in a noninvasive manner can aid in lesion detection, patient stratification, new drug development/validation, dose optimization, and treatment monitoring. This review summarizes the current status in multimodality imaging of the HER-kinase axis using PET, SPECT, optical, and MR imaging. The targeting ligands used include small-molecule tyrosine kinase inhibitors, peptides, proteins, antibodies, and engineered antibody fragments. EGFR and HER2 imaging have been well documented in the past, and imaging of HER3, HER4, HER heterodimers, and HER-kinase mutants deserves significant research effort in the future. Successful development of new HER-kinase-targeted imaging agents with optimal in vivo stability, targeting efficacy, and desirable pharmacokinetics for clinical translation will enable maximum benefit in cancer patient management.
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Affiliation(s)
- Weibo Cai
- The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd, P095, Stanford, CA 94305-5484, USA.
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Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB, Tice DA, Chen X. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging 2007; 34:2024-36. [PMID: 17673999 DOI: 10.1007/s00259-007-0503-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2007] [Accepted: 05/29/2007] [Indexed: 12/22/2022]
Abstract
PURPOSE EphA2 receptor tyrosine kinase is significantly overexpressed in a wide variety of cancer types. High EphA2 expression has been correlated with increased metastatic potential and poor patient survival. Although many recent reports have focused on blocking the EphA2 signaling pathway in cancer, the in vivo imaging of EphA2 has not yet been investigated. METHODS We labeled 1C1, a humanized monoclonal antibody against both human and murine EphA2, with (64)Cu through the chelating agent 1,4,7,10-tetraazacyclododecane N,N',N'',N'''-tetraacetic acid (DOTA) and carried out positron emission tomography (PET) imaging of eight tumor models with different EphA2 expression levels. Western blotting of tumor tissue lysate was performed to correlate the EphA2 expression level with (64)Cu-DOTA-1C1 uptake in the tumors. Immunofluorescence staining and biodistribution studies were also carried out to validate the in vivo results. RESULTS The radiolabeling yield was 88.9 +/- 9.5% (n = 7) and the specific activity of (64)Cu-DOTA-1C1 was 1.32 +/- 0.14 GBq/mg of 1C1 mAb. The antibody retained antigen-binding affinity/specificity after DOTA conjugation as measured by FACS analysis. The uptake of (64)Cu-DOTA-1C1 in CT-26 tumors was as high as 25.1 +/- 2.5 %ID/g (n = 3) at 18 h post injection. (64)Cu-DOTA-IgG, an isotype-matched control, exhibited minimal non-specific uptake in all eight tumor models. In vivo EphA2 specificity of (64)Cu-DOTA-1C1 was confirmed by successful blocking of CT-26 tumor uptake by unlabeled 1C1. Most importantly, the tumor uptake value obtained from PET imaging had excellent linear correlation with the relative tumor tissue EphA2 expression level measured by Western blot, where r (2) equals 0.90 and 0.92 at 18 h and 42 h post injection, respectively. CONCLUSION The tumor uptake of (64)Cu-DOTA-1C1 measured by microPET imaging reflects tumor EphA2 expression level in vivo. This is, to our knowledge, the first report of quantitative radioimmunoPET imaging of EphA2 in living subjects. Future clinical investigation of (64)Cu-DOTA-1C1 is warranted.
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Affiliation(s)
- Weibo Cai
- Department of Radiology and Bio-X Program, The Molecular Imaging Program at Stanford, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305-5484, USA
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Liu G, Dou S, He J, Liu X, Rusckowski M, Hnatowich DJ. Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice. Eur J Nucl Med Mol Imaging 2007; 34:237-46. [PMID: 17021815 PMCID: PMC1808331 DOI: 10.1007/s00259-006-0222-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
PURPOSE Pretargeting with phosphorodiamidate morpholino oligomers (MORFs) involves administration of a MORF-conjugated anti-tumor antibody such as MN14 as a pretargeting agent before that of the radiolabeled complementary MORF (cMORF) as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are the four pretargeting variables. The goal of this study was to develop a semiempirical description capable of predicting the biodistribution of the radiolabeled effector in pretargeted mice and then to compare predictions with experimental results from pretargeting studies in tumored animals in which the pretargeting interval and the detection time were both fixed but the dosages of both the effector and the pretargeting agent were separately varied. METHODS Pretargeting studies in LS174T tumored mice were performed using the anti-CEA antibody MN14 conjugated with MORF and the cMORF radiolabeled with (99m)Tc. A description was developed based on our previous observations in the same mouse model of the blood and tumor levels of MORF-MN14, accessibility of MORF-MN14 to labeled cMORF, the tumor accumulation of labeled cMORF relative to MORF-MN14 levels therein, and the kidney accumulation of labeled cMORF. The predicted values were then compared with the experimental values. RESULTS The predicted biodistribution of the radiolabeled effector and the experimental data were in gratifying agreement in normal organs, suggesting that the description of the pretargeting process was reliable. The tumor accumulations occasionally fell outside two standard deviations of that predicted, but after tumor size correction, good agreement between predicted and experimental values was observed here as well. CONCLUSION A semiempirical description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. We believe that the approach described herein may be applied to any of the alternative pretargeting approaches and animal tumor models currently under investigation. Furthermore, appreciation of the concepts may provide a rationale for selecting dosages and timings in human pretargeting studies as an alternative to pure empirical means.
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Affiliation(s)
- Guozheng Liu
- Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0243, USA.
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Goldenberg DM, Chatal JF, Barbet J, Boerman O, Sharkey RM. Cancer Imaging and Therapy with Bispecific Antibody Pretargeting. UPDATE ON CANCER THERAPEUTICS 2007; 2:19-31. [PMID: 18311322 PMCID: PMC2034280 DOI: 10.1016/j.uct.2007.04.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or 1-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (3 Fab's) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called Dock and Lock (DNL).
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Affiliation(s)
- David M Goldenberg
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ, USA
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Goldenberg DM, Sharkey RM, Paganelli G, Barbet J, Chatal JF. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J Clin Oncol 2005; 24:823-34. [PMID: 16380412 DOI: 10.1200/jco.2005.03.8471] [Citation(s) in RCA: 251] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
This article reviews the methods of pretargeting, which involve separating the targeting antibody from the subsequent delivery of an imaging or therapeutic agent that binds to the tumor-localized antibody. This provides enhanced tumor:background ratios and the delivery of a higher therapeutic dose than when antibodies are directly conjugated with radionuclides, as currently practiced in cancer radioimmunotherapy. We describe initial promising clinical results using streptavidin-antibody constructs with biotin-radionuclide conjugates in the treatment of patients with malignant gliomas, and of bispecific antibodies with hapten-radionuclides in the therapy of tumors expressing carcinoembryonic antigen, such as medullary thyroid and small-cell lung cancers.
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Affiliation(s)
- David M Goldenberg
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA.
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Liu G, He J, Dou S, Gupta S, Rusckowski M, Hnatowich DJ. Further investigations of morpholino pretargeting in mice--establishing quantitative relations in tumor. Eur J Nucl Med Mol Imaging 2005; 32:1115-23. [PMID: 16133391 PMCID: PMC1587614 DOI: 10.1007/s00259-005-1853-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE This laboratory has previously published on phosphorodiamidate morpholino (MORF) pretargeting of tumor in which an anti-tumor antibody conjugated with MORF (a DNA analogue) is first administered, followed at a later time by the radiolabeled complementary MORF (cMORF) as the effector. In the present study, the pharmacokinetics of the antibody and effector were measured under different conditions in mice to establish their quantitative relationships with tumor accumulations by pretargeting. METHODS A cytosine-free 18 mer cMORF was conjugated with MAG(3) for (99m)Tc labeling while the anti-CEA antibody MN14 was conjugated with DTPA for (111)In labeling and with MORF to impart binding affinity for radiolabeled cMORF. Mice bearing LS174T thigh tumors were used to study: (1) the pharmacokinetics of MN14-MORF by administering (111)In-MN14 at doses between 10 and 100 mug with sacrifice at 2 days and at 30 microg with sacrifice between 1 and 3 days; (2) the biodistribution of (99m)Tc-cMORF following one to four injections (containing 0.15 microg each and separated by 1 h) to animals having received 30 microg of antibody-MORF 2 days earlier and with sacrifice at 3 h after the final injection; and (3) the influence on the biodistribution of (99m)Tc-cMORF of a 2 to 4 day interval between the administration of 30 microg of antibody-MORF and 0.30 microg of (99m)Tc-cMORF. RESULTS (1) The biodistribution of antibody in percent accumulation (%ID or %ID/g) was largely independent of antibody dose but the absolute accumulation of antibody in tumor increased linearly with dose, showing no evidence of tumor saturation of CEA sites by MN14. Over 1-3 days post antibody administration, blood levels of radiolabeled antibody decreased as expected; however, tumor levels remained constant, thus showing an absence of antibody clearance in tumor over this period. (2) With fixed antibody-MORF dose and increasing number of injections of (99m)Tc-cMORF, cumulative percent blood levels steadily decreased in agreement with the values calculated based on the antibody-MORF in blood. In contrast, cumulative percent tumor levels stayed fairly constant over the first two injections. Thus the antibody-MORF in tumor became saturated with cMORF more slowly than that in blood owing to delivery differences. (3) As expected, percent blood levels decreased with increasing interval between injections of antibody-MORF and (99m)Tc-cMORF. The percent tumor accumulation, however, remained constant over the 3 day interval, thus demonstrating only slow loss of MORF expression in situ. The (99m)Tc-cMORF accumulation in tumor after saturation was mathematically determined based on the antibody-MORF concentration in tumor while the blood levels of (99m)Tc-cMORF were determined based on the concentration of antibody-MORF in blood. CONCLUSION Contrary to conclusions arrived at in our earlier study, the results of this study show that tumor CEA sites were not saturated even at the highest antibody dose investigated, that accessibility of MORF sites in tumor by (99m)Tc-cMORF was unhindered and that the maximum percent tumor accumulation of (99m)Tc-cMORF depended only on the tumor delivery efficiency of (99m)Tc-cMORF.
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Affiliation(s)
- Guozheng Liu
- Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0243, USA.
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Li GP, Zhang H, Zhu CM, Zhang J, Jiang XF. Avidin-biotin system pretargeting radioimmunoimaging and radioimmunotherapy and its application in mouse model of human colon carcinoma. World J Gastroenterol 2005; 11:6288-94. [PMID: 16419157 PMCID: PMC4320332 DOI: 10.3748/wjg.v11.i40.6288] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the multi-step pretargeting radioimm-unoimaging (RII) and radioimmunotherapy (RIT) in nude mice bearing human colon carcinoma with avidin-biotin system labeled with 153Sm.
METHODS: Two- and three-step strategies for avidin-biotin system pretargeting techniques were established. In a three-step procedure, human colon carcinoma bearing nude mice were first injected with biotinylated monoclonal antibody (McAb-Bt) followed by cold avidin (Av) 48 h later and then 153Sm-DB2 24 h thereafter; whereas the two-step procedure consisted of injection of 153Sm-SA 48 h after pretargeting with biotinylated anti-CEA monoclonal antibody (CEA McAb-Bt). SPECT imaging and biodistribution were performed at 4, 24, 48, or 72 h after injection of 153Sm-labeled compounds. Five groups of nude mice subcutaneously grafted with human colon carcinoma were treated 3 d after grafting. One group received the injection with 100 μg CEA McAb-Bt followed by cold avidin (80 μg) after 2 d and 11.1 MBq 153Sm-DB2 after 1 d. Four control groups were treated respectively with 11.1 MBq 153Sm-CEA McAb, 11.1 MBq 153Sm-nmIgG, 11.1 MBq 153Sm-DB2, 100 μL normal saline. Toxicity was evaluated by changes of leukocyte count, and the efficacy by variation in tumor volume. Histological analyses of tumors were performed.
RESULTS: The three-step procedure allowed faster blood clearance and yielded higher tumor blood ratios (5.76 at 4 h and 12.94 at 24 h) of the 153Sm-DB2. The tumor was clearly visualized at 4 h in γ-imaging after the injection of 153Sm-DB2, while a significant accumulation of 153Sm-SA in the tumor was observed only 24 h after the injection and tumor blood ratios at 4 and 24 h were 1.00 and 2.03, respectively, in the two-step procedure. Pretargeting RIT and 153Sm-CEA McAb had a strong tumor-inhibiting effect. The tumor inhibitory rate was 80.67% and 78.44%, respectively, five weeks after therapy. Histopathological evidence also indicated radioactive damage in tumor tissues as necrosis of tumor cells, while in the other organs such as liver and kidney no radioactive damage was observed. Leukocyte counts showed significant decrease after treatment in groups of 153Sm-CEA McAb and 153Sm-nmIgG.
CONCLUSION: The two kinds of pretargeting strategies can elevate the target-to-nontarget ratio, decrease the blood background and shorten the imaging time compared to 153Sm-CEA McAb. Three-step pretargeting RIT is as efficient as 153Sm-CEA McAb, but markedly less toxic. This study provides experimental evidence for the clinical application of pretargeting RII and RIT.
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Affiliation(s)
- Gui-Ping Li
- Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China.
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Wang Z, Mårtensson L, Nilsson R, Bendahl PO, Lindgren L, Ohlsson T, Sjögren HO, Strand SE, Tennvall J. Blood Pharmacokinetics of Various Monoclonal Antibodies Labeled with a New Trifunctional Chelating Reagent for Simultaneous Conjugation with 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid and Biotin before Radiolabeling. Clin Cancer Res 2005; 11:7171s-7177s. [PMID: 16203818 DOI: 10.1158/1078-0432.ccr-1004-0001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Knowledge of the blood pharmacokinetics of monoclonal antibodies is crucial in deciding the optimal time for starting the administration of a "clearing agent" or using a "clearing device." The primary purpose was to investigate whether the pharmacokinetics of various antibodies labeled with the same chelator and (111)In differed significantly after i.v. injection in immunocompetent rats. A new trifunctional chelator called "1033" containing a biotin and a radiometal chelation moiety is introduced, making it possible to use only one conjugation procedure for the antibody. EXPERIMENTAL DESIGN Sixty-five non-tumor-bearing rats were included and divided into four groups (I-IV). The blood pharmacokinetics was investigated for rituximab, BR96, and trastuzumab labeled with 1033 and (111)In (I-III). The whole-body activity and activity uptake in muscle, liver, and kidney, which might explain differences in the early pharmacokinetics in blood, were also measured. hMN14 labeled with another chelator [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)], but with the same radionuclide ((111)In-biotin-DOTA-hMN14), was studied (IV). The blood pharmacokinetics from another 15 tumor-bearing rats was compared with those of non-tumor-bearing rats (III) by injection of (111)In-1033-BR96. RESULTS No statistical difference was detected between the groups regarding the blood pharmacokinetics of rituximab, BR96, or trastuzumab. The pharmacokinetics and biodistribution of (111)In-biotin-DOTA-hMN14 exhibited a clear difference compared with others. There were no significant differences in the blood pharmacokinetics of (111)In-1033-BR96 between tumor-bearing rats and non-tumor-bearing rats. CONCLUSIONS Different antibodies labeled with the trifunctional chelator 1033 and (111)In did not exhibit different blood pharmacokinetics, which means that the pharmacokinetics could be predicted irrespective of the IgG1 antibody chosen. A small tumor burden did not change the pharmacokinetics of the radioimmunoconjugates.
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Affiliation(s)
- Zhongmin Wang
- Department of Oncology, Lund University Hospital, Sweden
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Lindén O, Kurkus J, Garkavij M, Cavallin-Ståhl E, Ljungberg M, Nilsson R, Ohlsson T, Sandberg B, Strand SE, Tennvall J. A Novel Platform for Radioimmunotherapy: Extracorporeal Depletion of Biotinylated and 90Y-Labeled Rituximab in Patients with Refractory B-Cell Lymphoma. Cancer Biother Radiopharm 2005; 20:457-66. [PMID: 16114994 DOI: 10.1089/cbr.2005.20.457] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Radioimmunotherapy is limited by the absorbed dose to radiosensitive organs. Removal of circulating radiolabeled MAbs after tumor tissue has been optimally targeted and should permit the administration of higher radioactivity to patients, resulting in a higher absorbed tumor dose. A novel "extracorporeal affinity adsorption treatment" (ECAT) device (MitraDep)was tested, with which biotinylated and radiolabeled MAbs can be removed from the circulation by passing whole blood over a filter coated with avidin. The antibodies were simultaneously radiolabeled and biotinylated using a trifunctional moiety comprising DOTA and biotin. Eight patients--all but 1 of whom with aggressive or mantle cell B-cell lymphoma-- who had failed to respond to standard therapies received infusions of 250 mg/m(2) cold rituximab and 150 MBq (111)In-rituximab-biotin for immunoscintigraphy. A week later, the patients were treated with another 250 mg/m(2) rituximab followed by (111)In/-(90)Y-rituximab-biotin (11 or 15 (90)Y MBq/kg). ECAT was performed 48 hours later. All 8 patients receiving (111)In-rituximab-biotin showed tumor uptake. Seven patients received radioimmunotherapy and subsequent ECAT. The mean depletion of (90)Y-rituximab-biotin in whole blood after ECAT was 96%, in the whole body 49%, in the lungs 62%, and in the liver and kidneys 40%. No effects on patients' vital signs and no adverse effects on hematological or coagulation parameters was observed during the ECAT procedure. A dose-escalation study is initiated.
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Affiliation(s)
- Ola Lindén
- Department of Oncology, Lund University Hospital, Lund, Sweden
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Sharkey RM, Karacay H, Chang CH, McBride WJ, Horak ID, Goldenberg DM. Improved therapy of non-Hodgkin's lymphoma xenografts using radionuclides pretargeted with a new anti-CD20 bispecific antibody. Leukemia 2005; 19:1064-9. [PMID: 15815716 DOI: 10.1038/sj.leu.2403751] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
A comparison of the therapeutic efficacy of a new bispecific monoclonal antibody (bsMAb)-pretargeting system vs the conventional direct targeting modality was undertaken. A bsMAb was made by coupling the Fab' of a humanized anti-CD20 antibody to the Fab' of a murine antibody directed against the peptide histamine-succinyl-glycine (HSG). The tumor targeting of the bsMAb was separated from the subsequent delivery of the radionuclide-bearing HSG peptide conjugated with (111)In or (90)Y. Nude mice bearing s.c. Ramos human B-cell lymphomas were injected with the bsMAb and then, 48 h later, (111)In/(90)Y-HSG peptide was given. At 3 h postinjection, tumor/blood ratios for pretargeted (111)In-HSG-peptide were similar to that observed with the directly conjugated (111)In-anti-CD20 IgG at its highest level on day 7, but by day 1, tumor/blood ratios were about 10-fold higher than the IgG. Tumors progressed rapidly in animals given 800 microCi of (90)Y-HSG peptide alone, whereas 5/10 animals in the group pretargeted by the anti-CD20 bsMAb were tumor-free 18 weeks later. The antitumor response in animals administered the pretargeted (90)Y-HSG peptide was also significantly superior to treatment with the directly radiolabeled (90)Y-anti-CD20 IgG, whether given as a single injection (P<0.007) or as a divided dose (P=0.016). This bsMAb-pretargeting procedure significantly improves the therapeutic response of targeted radionuclides in non-Hodgkin's lymphoma, warranting further development of this method of radioimmunotherapy.
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MESH Headings
- Animals
- Antibodies, Bispecific/pharmacology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized
- Antigens, CD20/immunology
- Disease Models, Animal
- Female
- Humans
- Immunoglobulin G/pharmacology
- Indium Radioisotopes/pharmacology
- Lymphoma, Non-Hodgkin/mortality
- Lymphoma, Non-Hodgkin/radiotherapy
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Radioimmunotherapy/methods
- Xenograft Model Antitumor Assays
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Affiliation(s)
- R M Sharkey
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 10709, USA
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