Abstract
ABSTRACTT-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.
Highlights
Trastuzumab has significantly improved patient outcomes in breast cancer, and has been a key in the design and implementation of other targeted therapies.[1]
In osteosarcoma and Ewing’s sarcoma, where high levels of HER2 expression was associated with decreased survival,[5] trastuzumab has not shown any benefit even when used in conjunction with cytotoxic chemotherapy.[6]
The light chain was constructed by extending the trastuzumab IgG1 light chain with a C-terminal (G4S)[3] linker followed by huOKT3 scFv.[20]
Summary
Trastuzumab has significantly improved patient outcomes in breast cancer, and has been a key in the design and implementation of other targeted therapies.[1] HER2 expression does not guarantee a clinical response to trastuzumab or other HER2-targeted therapies.[2,3] HER2-positive breast cancer patients with metastatic disease initially respond to trastuzumab and/or other HER2-targeted therapies, but almost all eventually will develop resistance and relapse.[4] In osteosarcoma and Ewing’s sarcoma, where high levels of HER2 expression was associated with decreased survival,[5] trastuzumab has not shown any benefit even when used in conjunction with cytotoxic chemotherapy.[6] trastuzumab, like other HER-targeted therapies, has shown modest or no benefit against HER2(C) positive head and neck cancer.[7]. A different approach, one that selectively targets malignant cells that overexpress HER family receptors, and that can generate cytotoxic antitumor responses independently of the receptor activation status could be beneficial
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