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

• Published in: Angewandte 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
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 08.06.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Activation; Amino acids; Antibodies; Antikörper; Antikörper-Wirkstoff-Konjugate; Breast; Breast cancer; Brustkrebs; Cancer; Chemistry; Effectiveness; Format; Human; Nichtnatürliche Aminosäuren; Rodents; T cell receptors; T-Zell-Aktivierung
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201500799

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.