Abstract 5040: Novel HER3 targeting antibody radioconjugates, 225Ac-HER3 ARC and 177Lu-HER3 ARC, exhibit potent antitumor efficacy in HER3-positive solid tumors

Abstract Background: HER3 is a unique member of the EGFR family that collaborates with other EGFR receptors to induce tumorigenesis and drug resistance. Moreover, HER3 expression is linked to poor survival for patients with solid tumors. Despite HER3 being a rational cancer therapeutic target, no HER3-directed therapies have been approved for clinical use. However, new therapeutic strategies such as antibody drug conjugates (ADCs) are being investigated. Targeted radiotherapy, including radiolabeled antibodies (ARCs), is unique mechanistically by inducing cell death independent of biologic pathway inhibition, and can be efficacious with less toxicity relative to other therapeutic modalities. Therefore, we hypothesized that the cytotoxic effects of alpha (225Ac) or beta (177Lu) emitting radionuclides combined with the specificity of anti-HER3 antibody targeting is a compelling therapeutic approach for HER3-expressing tumors. Here we evaluated the antitumor effects of 225Ac or 177Lu armed HER3 ARCs across multiple HER3-expressing cancer models such as ovarian, colorectal, prostate, and renal cancer. Methods: ARCs were prepared by radiolabeling AT-02, an anti-HER3 antibody, with 225Ac or 177Lu using p-SCN-Bn-DOTA to yield 225Ac or 177Lu-HER3 ARC. The binding activity and tumor cell cytotoxicity of HER3 ARCs were assessed by ELISA using human recombinant HER3, flow cytometry on HER3-expressing cells, and colony forming assays. To evaluate the antitumor growth effects of 225Ac-HER3 and 177Lu-HER3 ARCs in vivo, preclinical human tumor xenograft models were developed. Mice bearing HER3-positive tumors were dosed with 225Ac-HER3 ARC (0.2 or 0.4 µCi), or 177Lu-HER3 ARC (200 or 400 µCi) and tumor growth and body weight was monitored. Results: The pharmacological binding properties of HER3 antibody radiolabeled with 225Ac or 177Lu were similar to that of unmodified antibody as demonstrated by HER3 binding ELISA and flow cytometry. HER3 ARCs induced cytotoxicity and inhibited colony formation of HER3-positive tumor cell lines. Significant in vivo human tumor xenograft growth inhibition was observed in response to 225Ac or 177Lu HER3 ARCs compared to control groups (unmodified AT02 or IgG ARCs) in the models studied. No significant loss of body weight was observed in mice treated with HER3 ARCs suggesting that all treatments were well tolerated. Conclusions: In this study, both 225Ac-HER3 ARC and 177Lu-HER3 ARC demonstrated significant antitumor activity against HER3-expressing tumors in a dose-dependent manner. The HER3 targeted radiotherapy approach that we have undertaken could potentially overcome the limitations of current solid tumor therapies in resistance settings and warrants further evaluation in patients with HER3-expressing tumors. Citation Format: Denis Beckford-Vera, Megan McCloskey, Jason Li, Caroline Jennings, Le-Cun Xu, Debbie Lewis, Patrik Brodin, Amanda Chin, Monideepa Roy, Mary Chen, Helen Kotanides. Novel HER3 targeting antibody radioconjugates, 225Ac-HER3 ARC and 177Lu-HER3 ARC, exhibit potent antitumor efficacy in HER3-positive solid tumors. [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 5040.