title: Redirected lysis of human melanoma cells by a MCSP/CD3-bispecific BiTE antibody that engages patient-derived T cells.
abstract: Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.
authors: Department of Melanoma Research, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA. itakurah@jwci.org
authors: Hitoe
authors: H
authors: Torisu-Itakura
authors: Hans F
authors: HF
authors: Schoellhammer
authors: Myung-Shin
authors: MS
authors: Sim
authors: Reiko F
authors: RF
authors: Irie
authors: Susanne
authors: S
authors: Hausmann
authors: Tobias
authors: T
authors: Raum
authors: Patrick A
authors: PA
authors: Baeuerle
authors: Donald L
authors: DL
authors: Morton
mesh_terms: D000328:Adult; D000368:Aged; D018033:Antibodies, Bispecific / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D017252:CD3 Complex; D000099216:Chondroitin Sulfate Proteoglycan 4