title: Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody.
abstract: T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Itsin vitrotumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). Thein vivoandin vitroantitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Lopez-Albaitero
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Hongfen
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Hoa
authors.initials: H
authors.lastname: Tran
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Janjigian
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
keywords: Bispecific antibody; CD3; HER2; T cells; immunotherapy