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Angew Chem Int Ed Engl. 2015 Jun 8;54(24):7022-7. doi: 10.1002/anie.201500799. Epub 2015 Apr 27.

Multiformat T-cell-engaging bispecific antibodies targeting human breast cancers.

Author information

1
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
2
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
3
Department of Immunology and Microbial Science, The Scripps Research Institute (USA).
4
EuCode Technology, Ambrx, Inc. 10975 N Torrey Pines Rd, La Jolla, CA 92037 (USA).
5
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037 (USA). Schultz@scripps.edu.
6
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA). Schultz@scripps.edu.
7
California Institute for Biomedical Research, 11119 N Torrey Pines Rd, La Jolla, CA 92037 (USA). chkim@calibr.org.

Abstract

Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression.

KEYWORDS:

T-cell activation; antibody drug conjugates; bispecific antibodies; breast cancers; noncanonical amino acids

PMID:
25919418
PMCID:
PMC4492699
DOI:
10.1002/anie.201500799
[Indexed for MEDLINE]
Free PMC Article

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