Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody Journal Article
| Authors: | Lopez-Albaitero, A.; Xu, H.; Guo, H.; Wang, L.; Wu, Z.; Tran, H.; Chandarlapaty, S.; Scaltriti, M.; Janjigian, Y.; de Stanchina, E.; Cheung, N. K. V. |
| Article 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. Its in vitro tumor 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). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic. © 2017 The Author(s). Published with license by Taylor & Francis Group, LLC © 2017, © Andres Lopez-Albaitero, Hong Xu, Hongfen Guo, Linlin Wang, Zhihao Wu, Hoa Tran, Sarat Chandarlapaty, Maurizio Scaltriti, Yelena Janjigian, Elisa de Stanchina, and Nai-Kong V. Cheung. |
| Keywords: | t cells; immunotherapy; her2; cd3; bispecific antibody |
| Journal Title: | OncoImmunology |
| Volume: | 6 |
| Issue: | 3 |
| ISSN: | 2162-4011 |
| Publisher: | Landes Bioscience |
| Date Published: | 2017-03-10 |
| Start Page: | e1267891 |
| Language: | English |
| DOI: | 10.1080/2162402x.2016.1267891 |
| PROVIDER: | scopus |
| PMCID: | PMC5384386 |
| PUBMED: | 28405494 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2017 -- Source: Scopus |
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648Cheung -
394Janjigian -
277Chandarlapaty -
343De Stanchina -
53Xu -
73Guo -
169Scaltriti -
6Tran -
6Wu -
4Wang
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