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Anti‐CD3‐based bispecific antibody designed for therapy of human B‐cell malignancy can induce T‐cell activation by antigen‐dependent and antigen‐independent mechanisms
Journal article   Peer reviewed

Anti‐CD3‐based bispecific antibody designed for therapy of human B‐cell malignancy can induce T‐cell activation by antigen‐dependent and antigen‐independent mechanisms

Brian K Link, Sheri A Kostelny, Michael S Cole, William P Fusselman, J. Yun Tso and George J Weiner
International journal of cancer, Vol.77(2), pp.251-256
07/17/1998
DOI: 10.1002/(SICI)1097-0215(19980717)77:2<251::AID-IJC14>3.0.CO;2-E
PMID: 9650561

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Abstract

Anti‐CD3 × anti‐B‐cell antigen bispecific monoclonal antibodies (bsAbs) can redirect T‐cell‐mediated lysis toward malignant B cells. Clinical trials with CD3‐based bsAbs have shown toxicity in patients which is likely related to non‐specific T‐cell activation and targeting. Our current studies were designed to explore the mechanisms responsible for the observed in vivo toxicity by evaluating the immunologic effects of 2 different bsAb preparations in vitro. 1D10 was used as the tumor specific arm of the bsAbs. This antibody reacts with a variant of HLA‐DR found on a majority of pre‐B‐ and B‐cell malignancies, and normal B cells in some individuals. Anti‐CD3 served as the T‐cell specific arm. A 1D10 × anti‐CD3 bispecific IgG (bsIgG) produced using the hybrid‐hybridoma method was compared to a 1D10 × anti‐CD3 bispecific F(ab′)2 [bsF(ab′)2] produced using the leucine zipper technique. In cytotoxicity assays, both bsIgG and bsF(ab′)2 induced lysis by pre‐activated T cells of 1D10 (+) malignant B cells. bsIgG at high concentrations also induced lysis of 1D10 (−) tumor cells, while bsF(ab′)2 did not. Proliferation of T cells induced by bsIgG and bsF(ab′)2 was also evaluated. Both forms of bsAbs induced T‐cell proliferation in the presence of antigen (+) Raji cells, while only bsIgG did so in the presence of antigen (−) malignant B cells. bsF(ab′)2 induced T‐cell activation in the absence of any tumor cells when testing was performed on samples where the 1D10 target antigen was present on normal peripheral blood B cells. We conclude that non‐specific T‐cell activation from bsAbs can occur in an antigen‐independent manner due to the Fc/Fc receptor (FcR) interaction, or in an antigen‐dependent manner when antigen is expressed on normal or tumor cells. Both mechanisms may have been responsible for the toxicity observed in prior clinical studies. Int. J. Cancer77:251–256, 1998. © 1998 Wiley‐Liss, Inc.

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