Abstract 3168: Fully human anti-HER-2 antibodies to HER-2 domains distinct from trastuzumab as antibody drug conjugates for tumor growth inhibition

Abstract HER2 is a receptor overexpressed in several cancers with prognostic and predictive implications as it is associated with shorter disease-free and overall survivals, resistance to hormonal agents and increased risk of brain metastasis. Trastuzumab is a humanized anti-HER2 neutralizing monoclonal antibody binding to domain IV of HER2 extracellular region. While first FDA approved as a naked antibody, it is at the basis of the development of several antibody drug conjugates bearing different linker and payloads such Ado-Trastuzumab-Emtansine (Kadcyla) and fam-trastuzumab-deruxtecan-nhki (Enhertu). Thus, it would be interesting to develop antibodies to different domains of Her2 which could be used as ADCs as an alternative or even potentiators of trastuzumab based ADCs. We are reporting here the development of fully human internalizing anti-Her2 antibodies that bind to HER2 domain distinct from domain IV, the trastuzumab binding site. These antibodies have been developed by immunizing humanized transgenic mice with recombinant Her2 protein. The screening process included inhibition of binding of trastuzumab to Her2 by enzyme linked immunoassay and by Octet epitope binning as well as internalization assay. Several internalizing antibodies not competing with trastuzumab and with high affinity (Kd ranging from 10-9 M to 10-12 M) were selected. Their applications as antibody drug conjugates were examined with several HER2 overexpressing breast and gastric cancer cells. Two trastuzumab noncompeting antibodies were further characterized for their ability to inhibit proliferation in vitro and in vivo in mouse xenografts studies and to potentiate trastuzumab effect. Our data also demonstrates that the use of fully human mice constitutes a powerful approach to develop fully human monoclonal antibodies against cancer targets allowing to by-pass the need for humanization and affinity maturation of antibodies. Citation Format: Ginette Serrero, Jianping Dong, Jun Hayashi. Fully human anti-HER-2 antibodies to HER-2 domains distinct from trastuzumab as antibody drug conjugates for tumor growth inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3168.