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Abstract 3306: Targeting HER3 receptor positive cancers with a novel anti-HER3 antibody radioconjugate (ARC)


 Background: HER3 overexpression is reported to be associated with poor survival in breast, ovarian, lung, gastric and prostate cancer. In addition, upregulation of HER3 in response to HER1 or HER2 targeted therapies, is implicated in the acquired resistance against these therapies. Therefore, effective targeting of HER3 can potentially overcome resistance and enhance therapeutic efficacy. Although a number of anti-HER3 antibodies have failed clinical testing with the development focus being shifted to other approaches such as antibody drug conjugates and bispecific antibodies, there are currently no approved HER3-targeted therapies. Here we describe a novel approach that can enhance therapeutic efficacy in HER3+ cancer patients by conjugating an anti-HER3 antibody with the alpha-emitting cytotoxic radioisotope Actinium-225 (225Ac) to create an anti-HER3 antibody radiation conjugate (225Ac-HER3-ARC). Alpha emitting radioisotopes like 225Ac can cause double-strand DNA breaks for which there is no known resistance mechanism. Due to the cytotoxic properties of the radioisotope, lower levels of antibody may be needed, resulting in reduced incidence or less severe toxicities. We hypothesize that targeting HER3 in solid tumors with an ARC will result in tumor specific cell killing especially in a setting where HER-targeting agents are not a viable option. We developed a novel 225Ac-HER3-ARC and evaluated its efficacy in HER3+ in vitro and in vivo tumor models.
 Methods: AT-02, an anti-HER3 antibody, was conjugated with p-SCN-Bn-DOTA and radiolabeled with 225Ac. 225Ac-HER3-ARC specific binding to HER3 was assessed by ELISA using human recombinant HER3 and by flow cytometry on HER3+ cells. The cytotoxic effect of HER3 ARC was evaluated in a panel of HER3 expressing cells. We further evaluated the maximum tolerated dose and therapeutic efficacy of the ARC in nude mice bearing human HER3+ xenograft tumors.
 Results: In this study we successfully radiolabeled anti-HER3 with 225Ac. 225Ac-HER3-ARC showed similar binding properties to those of the native antibody by ELISA (HER3-ARC: EC50 = 0.0017 µg/ml, HER3 EC50 = 0.0022 µg/ml) and flow cytometry. Treatment with ARC was cytotoxic to HER3+ cells in a dose-dependent manner (EC50 = 54 kBq/ml). 225Ac-HER3-ARC showed potent in vivo efficacy in preclinical solid tumor xenograft models that was correlated with the in vitro cytotoxicity findings. Treatment with 225Ac-HER3-ARC (7.4 - 22.2 kBq, 200 - 600 nCi) led to complete responses and significantly prolonged survival compared to control groups (p < 0.0001).
 Conclusions: Our findings demonstrate that targeting HER3 with a novel 225Ac-HER3-ARC results in potent tumor cell cytotoxicity and complete anti-tumor response in HER3 tumor xenograft model. This approach provides a promising therapeutic strategy for HER3 positive tumors and warrants further assessment.
 Citation Format: Denis Beckford-Vera, Jason Li, Megan McCloskey, Caroline Jennings, Amanda Chin, Qing Liang, Jesse Hwang, Monideepa Roy, Mary Chen, Helen Kotanides. Targeting HER3 receptor positive cancers with a novel anti-HER3 antibody radioconjugate (ARC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3306.