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

Abstract

INTRODUCTION:

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.

MATERIALS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Hillary E Lum, Mendy Miller, Pamela A Davol, Ryan C Grabert, James B Davis, Lawrence G Lum
• Journal: Anticancer research (Anticancer Res) 2005 Jan-Feb Vol. 25 Issue 1A Pg. 43-52 ISSN: 0250-7005 [Print] Greece
• PMID: 15816517 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Bispecific
• Antibodies, Monoclonal
• CD3 Complex
• Cytokines
• Immunoconjugates
• Receptor, ErbB-2

Topics

• Antibodies, Bispecific (immunology, pharmacology)
• Antibodies, Monoclonal (immunology, pharmacology)
• CD3 Complex (immunology)
• Cell Line, Tumor
• Cytokines (immunology, metabolism)
• Cytotoxicity, Immunologic (drug effects, immunology)
• Humans
• Immunization, Passive (methods)
• Immunoconjugates (immunology, pharmacology)
• Lymphocyte Activation (drug effects, immunology)
• Male
• Prostatic Neoplasms (immunology, metabolism, therapy)
• Receptor, ErbB-2 (immunology, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)