Abstract
Disitamab vedotin (DV, RC48-ADC) is an antibody-drug conjugate (ADC) that targets cancers expressing HER2, an oncogenic growth factor receptor that promotes cell proliferation and survival. DV consists of a novel anti-HER2 monoclonal antibody, disitamab, conjugated with the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a cleavable linker. DV has multimodal antitumor mechanisms of action that include direct cytotoxicity of HER2-expressing cancer cells and bystander effect based-cytotoxicity of neighboring cells, both of which are mediated by the intracellular release of MMAE within the targeted cell. Released MMAE can induce immunogenic cell death (ICD), which promotes immune cell recruitment to the tumor. In addition, DV stimulates Fc-gamma receptor mediated antibody-dependent cellular cytotoxicity (ADCC), which can lead to target cell death. DV also inhibits HER2-activated downstream signaling pathways, further blocking cell growth and proliferation. In this preclinical study, we investigated the antitumor activity of DV in breast and gastric cancer models, both as a monotherapy and in combination with tucatinib, a HER2-selective oral tyrosine kinase inhibitor approved in combination with trastuzumab and capecitabine for patients with HER2+ metastatic breast cancer. In vitro, DV demonstrated cytotoxic activity against a panel of breast cancer cell lines with varying levels of HER2 expression, including the HER2-low range, and was more potent than the HER2-directed ADC trastuzumab emtansine (T-DM1). Internalization assays using time-lapse microscopy of breast cancer cells continuously exposed to labeled naked antibodies showed that disitamab internalized to a greater magnitude than trastuzumab. In a subset of those cell lines, DV showed enhanced internalization compared to other HER2-targeted ADCs, namely T-DM1 and trastuzumab deruxtecan (T-DXd). Similar internalization and cytotoxic activities of DV were observed in gastric cancer cell lines. We explored whether dual HER2 targeting with DV in combination with tucatinib improved the antitumor outcomes. In vitro results demonstrated evidence of enhanced cytotoxicity over single agents when tested in breast and gastric cancer cell lines with a wide range of HER2 expression levels. Investigation of the mechanism of the enhanced cytotoxicity revealed increased DV internalization in the presence of tucatinib, attributable to elevated HER2 levels upon treatment with tucatinib. Overall, these findings provide scientific rationale to explore DV in HER2-positive and HER2-low breast and gastric cancer settings as a monotherapy or in combination with tucatinib.
Citation Format: Kelsi Willis, Katie Snead, Robert Thurman, Margo Zaval, Anita Kulukian. Disitamab vedotin, an investigational HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy and in combination with tucatinib in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 560.
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