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


Authors: Santich, B. H.; Park, J. A.; Tran, H.; Guo, H. F.; Huse, M.; Cheung, N. K. V.
Article Title: Interdomain spacing and spatial configuration drive the potency of IgG-[L]-scFv T cell 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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Journal Title: Science Translational Medicine
Volume: 12
Issue: 534
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2020-03-11
Start Page: eaax1315
Language: English
DOI: 10.1126/scitranslmed.aax1315
PUBMED: 32161106
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 April 2020 -- Source: Scopus
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MSK Authors
  1. Nai-Kong Cheung
    531 Cheung
  2. Morgan Huse
    45 Huse
  3. Hong-Fen Guo
    39 Guo
  4. Hoa   Tran
    5 Tran
  5. Jeong A Park
    8 Park