Article

Preclinical studies comparing different bispecific antibodies for redirecting T cell cytotoxicity to extracellular antigens on prostate carcinomas

Boston University, Boston, Massachusetts, United States
Anticancer research (Impact Factor: 1.83). 01/2005; 25(1A):43-52.
Source: PubMed

ABSTRACT

Bispecific antibodies (BiAbs) are used to enhance targeting of T cells and other cytotoxic agents to tumors while minimizing non-specific tissue toxicities. This study compares the targeting efficacy of 3 BiAbs derived from chemically heteroconjugating a T cell-directed monoclonal antibody (mAb) to 9184, 9187 or 9189, which are mAbs directed at extracellular antigens expressed on human prostate carcinoma cell lines.
9184 (anti-Her2/neu), 9187 (anti-gp55) and 9189 (anti-gp42) were each heteroconjugated to anti-CD3 to produce BiAbs capable of binding to ("arming") anti-CD3 activated T cells (ATC) and redirecting their cytotoxicity to prostate cancer cells expressing the respective antigen. ATC from cancer patients and/or normal subjects were armed with each BiAb and tested in co-cultures with PC-3, DU 145, and LNCaP cells for binding, cytotoxicity, and cytokine secretion.
All 3 tumor-directed mAbs bound to each of the prostate cancer cell lines. ATC armed with 9184Bi statistically augmented cytotoxicity directed at PC-3 and increased IFN-gamma, TNF-alpha, and GM-CSF secretion as well as induced IFN-gamma EliSpots above that seen for 9187Bi, 9189Bi, ATC alone or ATC armed with an irrelevant BiAb. 9184Bi-armed ATC mediated significant cytotoxicity against LNCaP and DU 145 cells as well. When we armed ATC from 6 cancer patients with 9184Bi, 9184Bi markedly enhanced cytotoxicity of ATC from 5 of the 6 patients.
Arming ATC with BiAbs augments cytotoxicity directed at prostate cancer lines expressing the target antigens. Arming with 9184Bi was the most effective at redirecting cytotoxicity at PC-3 cells and inducing cytokine secretion. As an alternative to mAb therapy with anti-HER2, the HER2 antigen may provide a suitable target for redirecting anti-cancer immune cells, immunobiologicals, or other agents to HRPC.

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Available from: Hillary D Lum, Mar 13, 2015
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    • "Arming ATC with HER2Bi or EGFRBi converts every ATC into a specific cytotoxic T cell [3-7]. Our preclinical studies show that armed ATC can target breast [6], prostate [8], ovarian [5] EGFR+ cancers (head & neck, colorectal, pancreatic, lung [4], neuroblastomas [9], and CD20+ NHL [7]. ATC armed with HER2Bi were not only able to lyse cancer cells that have high (3+) expression of HER2 but more importantly target and lyse MCF-7 cells that express low or nil HER2 expression [6] Moreover, armed ATC can kill multiple times, secrete cytokines/chemokines and multiply after engaging tumor cells in vitro[10]. "
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