Abstract 3145: HRA00242-C004, a novel anti-PSMA ADC with high DAR reveals potent in vitro and in vivo anti-tumor efficacy

Abstract Prostate cancer (PCa) is the second most common cancer, and it is the fifth leading cause of cancer-related death among men. The incidence rates of PCa are 37.5 per 100,000 in developed countries and 11.3 per 100,000 in developing countries, while mortality rates are 8.1 per 100,000 in developed countries and 5.9 per 100,000 in developing countries1. As androgen receptor (AR) signaling plays an essential role in PCa initiation and disease progression, androgen deprivation therapy (ADT) has been a backbone of treatment for patients with advanced disease2. However, patient responses to ADT vary, and most patients eventually develop castration-resistant prostate cancer (CRPC) which remains large unmet clinical need3. Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein located on the cell membrane, is specifically and highly expressed in PCa with an extremely low expression level in non-prostatic tissues4, which makes it an ideal target for the treatment of PCa5.Here, we presented a PSMA-directed ADC, HRA00242-C004, which features a differentiated topoisomerase I inhibitor payload DXh conjugated via a cleavable linker to a humanized anti-PSMA IgG1 antibody (HRP04732). HRP04732 showed good binding affinity in both protein and cell-level assays, and a better cell internalization profile when compared with the reference antibody (AB-PG1-XG1-006, published sequences from US8114965B2). HRA00242-C004 exerted strong inhibition effect on cell lines with different PSMA expression levels. In vivo efficacy study, HRA00242-C004 showed potent anti-tumor activity in PSMA medium expression human prostate cancer 22RV1 xenograft model without significant weight loss during the experiments. Moreover, HRA00242-C004 demonstrated satisfactory PK profiles in SD rats and cynomolgus monkeys without any toxicity observed in PK assays. Compared with AB-PG1-XG1-006-DXh (the reference ADC), HRA00242-C004 exhibited a longer elimination half-life as well as higher serum exposure level of both the total antibody and the intact ADC. Meanwhile, as employing the same linker-payload as SHR-A1811, HRA00242-C004 has potential good plasma stability which was consistent with the results of PK study. In summary, with a highly permeable payload, high DAR, potent in vitro and in vivo anti-tumor efficacy, HRA00242-C004 demonstrated the best-in-class potential. 1.CA Cancer J. Clin. 2021, 71, 209-249.2.Nat. Rev. Urol. 2019, 16, 645-654.3.J. Clin. Oncol. 2015, 33, 1151-1156.4.World J Surg. 2006; 30: 628-36.5.Front Oncol. 2018; 8: 653-63. Citation Format: Guang Lin, Haoying Zhang, Zhibin Xu, Lingfeng You, Zhendong Xue, Yuchang Mao, Xiaoying Yang, Bing Hu, Sophie Lin, Jun Feng, Zhe Zhang, Xin Ye, Min Hu, Feng He. HRA00242-C004, a novel anti-PSMA ADC with high DAR reveals potent in vitro and in vivo anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3145.