Multiformat T-Cell-Engaging Bispecific Antibodies Targeting Human Breast Cancers

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 valen...

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Published inAngewandte Chemie Vol. 127; no. 24; pp. 7128 - 7133
Main Authors Cao, Yu, Axup, Jun Y., Ma, Jennifer S. Y., Wang, Rongsheng E., Choi, Seihyun, Tardif, Virginie, Lim, Reyna K. V., Pugh, Holly M., Lawson, Brian R., Welzel, Gus, Kazane, Stephanie A., Sun, Ying, Tian, Feng, Srinagesh, Shailaja, Javahishvili, Tsotne, Schultz, Peter G., Kim, Chan Hyuk
Format Journal Article
LanguageEnglish
German
Published Weinheim WILEY-VCH Verlag 08.06.2015
WILEY‐VCH Verlag
Wiley Subscription Services, Inc
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Summary: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. Bispezifische Antikörper wirken sehr gezielt auf Brustkrebszellen mit geringer Antigendichte. Es wird vorgeschlagen, dass das monovalente BiFab in Abwesenheit einer Fc‐Domäne das beste Format für bispezifische Antikörper ist, um die antigenabhängige T‐Zell‐Aktivierung auszulösen und die gezielte Beseitigung von Her2‐exprimierenden Tumoren zu bewirken.
Bibliography:This work was supported by NIH grant 5R01 GM062159-13 (P.G.S.).
ArticleID:ANGE201500799
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ark:/67375/WNG-N9BDTKWR-J
NIH - No. 5R01 GM062159-13
These authors contributed equally to this work.
This work was supported by NIH grant 5R01 GM062159‐13 (P.G.S.).
ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201500799