Research ArticleCancer

Interdomain spacing and spatial configuration drive the potency of IgG-[L]-scFv T cell bispecific antibodies

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Science Translational Medicine  11 Mar 2020:
Vol. 12, Issue 534, eaax1315
DOI: 10.1126/scitranslmed.aax1315

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The specifics of bispecifics

T cell–bispecific antibodies, which are designed to bring T cells together with tumor cells and thereby promote tumor killing, have been attracting increasing attention for a variety of tumor types. These bispecific antibodies come in a variety of shapes, sizes, and configurations, with different studies offering different suggestions as to factors that influence the antibodies’ effectiveness. Santich et al. undertook a systematic effort to assess the various parameters involved in the antitumor effectiveness of a particular bispecific antibody, examining factors such as valency and spatial configuration, which should help inform the development of future bispecific antibodies.

Abstract

T cell–bispecific antibodies (BsAbs) couple cytotoxic T lymphocytes to tumor cells, inducing their destruction. Although there are more than 60 classes of BsAbs in development, the relative importance of parameters such as interdomain spacing or spatial configuration is largely unknown. Here, we dissected a symmetric dual bivalent BsAb platform (IgG-[L]-scFv: antitumor IgG with anti-CD3 scFv fused to the light chains) to explore the importance of valency and spatial configuration for BsAb-induced T cell cytotoxicity. Our results revealed that placing tumor and T cell binding domains on the same side of a BsAb (cis-configuration) elicited substantially stronger antitumor activity, in vitro and in vivo, compared to positioning them on opposite sides (trans-configuration). Moreover, using two cis-modules in the same BsAb further improved cytotoxicity (up to 2000-fold). In addition, separating antigen-binding components with a single Ig domain (CL) markedly enhanced cytokine release and in vivo tumor responses compared to smaller (G4S1) or larger (CH1-CH2-CH3) spacers. These findings provide guidelines for improving BsAb function and highlight the importance of spatial configuration and dual bivalency as development parameters.

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