Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen
| Autor: | Petra Fluhr, Mirnalini Sriskandarajah, William B. Stallcup, Peter Kufer, Patrick A. Baeuerle, Claudia Bluemel, Susanne Hausmann |
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| Rok vydání: | 2010 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research CD3 Complex medicine.drug_class Recombinant Fusion Proteins T cell Immunology Epitopes T-Lymphocyte CHO Cells Biology Protein Engineering Monoclonal antibody Cancer Vaccines Epitope Cricetulus Antigen Antigens Neoplasm Cricetinae Antibodies Bispecific medicine Animals Humans Immunology and Allergy Cytotoxic T cell Melanoma Membrane Proteins Fusion protein Molecular biology medicine.anatomical_structure Chondroitin Sulfate Proteoglycans Oncology CSPG4 biology.protein Antibody Protein Binding Single-Chain Antibodies |
| Zdroj: | Cancer Immunology, Immunotherapy. 59:1197-1209 |
| ISSN: | 1432-0851 0340-7004 |
| DOI: | 10.1007/s00262-010-0844-y |
| Popis: | Melanoma chondroitin sulfate proteoglycan (MCSP; also called CSPG4, NG2, HMW-MAA, MSK16, MCSPG, MEL-CSPG, or gp240) is a surface antigen frequently expressed on human melanoma cells, which is involved in cell adhesion, invasion and spreading, angiogenesis, complement inhibition, and signaling. MCSP has therefore been frequently selected as target antigen for development of antibody- and vaccine-based therapeutic approaches. We have here used a large panel of monoclonal antibodies against human MCSP for generation of single-chain MCSP/CD3-bispecific antibodies of the BiTE (for bispecific T cell engager) class. Despite similar binding affinity to MCSP, respective BiTE antibodies greatly differed in their potency of redirected lysis of CHO cells stably transfected with full-length human MCSP, or with various MCSP deletion mutants and fusion proteins. BiTE antibodies binding to the membrane proximal domain D3 of MCSP were more potent than those binding to more distal domains. This epitope distance effect was corroborated with EpCAM/CD3-bispecific BiTE antibody MT110 by testing various fusion proteins between MCSP and EpCAM as surface antigens. CHO cells expressing small surface target antigens were generally better lysed than those expressing larger target antigens, indicating that antigen size was also an important determinant for the potency of BiTE antibody. The present study for the first time relates the positioning of binding domains and size of surface antigens to the potency of target cell lysis by BiTE-redirected cytotoxic T cells. In case of the MCSP antigen, this provides the basis for selection of a maximally potent BiTE antibody candidate for development of a novel melanoma therapy. |
| Databáze: | OpenAIRE |
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