Abstract 6356: Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC

Abstract

Abstract In response to genomic insults and DNA double-strand breaks, the stressed epithelial cells express the MHC I-chain related molecule (MIC) on the surface as a byproduct of activating the ATM pathway. The MIC molecule itself has no known impact on tumor survival or growth. In the context of immune microenvironment, tumor cell surface MIC can activate NK cells and co-stimulate CD8 T cells by engaging in the activating receptor NKG2D to hinder the early tumorigenesis. However, in established malignancies, in particular metastatic diseases, tumor cells shed surface MIC to release the soluble form MIC (sMIC). It has been well demonstrated that, in contrary to cell surface MIC, sMIC is highly immune suppressive by disturbing NK cell homeostasis and repolarizing NK cells function, impairing antigen-specific CD8 T cell function by downmodulating NKG2D expression and CD3z expression, and facilitating immune suppression of MDSCs and TAMs in tumor microenvironment. We have demonstrated that MIC is prevalently expressed by prostate tumor cells and significantly upregulated in mCRPC tumors. We have shown significantly elevated levels of serum sMIC in prostate cancer patients with metastatic diseases. We have developed a novel class of clinical candidate monoclonal antibody huB10G5 that can target both sMIC and surface MIC to re-invigorate both NK and CD8 T cell function and inhibit MDSCs and TAMs in preclinical models. The huB10G5 has an acceptable safety profile and is currently completing CMC for IND enabling. We hypothesize that huB10G5 is a novel immune therapeutic reagent for mCRPC patients. To test our hypothesis, we first conducted serial studies of the clinical candidate huB10G5 in pre-clinical models of prostate cancers. We found that huB10G5 can effectively induce 100% long-term tumor complete regression (CR) as low as 1.0 mg/KG. These animals are fully protected from tumor re-challenge. The anti-tumor effect is mediated by the combined action of NK and CD8 T cells. With the support of our pre-clinical efficacy and safety data, we have planned to initiate Phase I clinical trial with huB10G5 for mCRPC patients in 2024. Citation Format: Jennifer Donglan Wu, Jeff Sosman, Masha Kocherginsky, Anthony Serritella, Maha Hussian, David J. Vanderweele. Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC [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 6356.