Abstract P038: Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX

Poor vascularization of solid tumors leads to inadequate nutrient and oxygen supplies which forces tumor cells to reprogram their metabolism. Consequently, the tumor cell9s environment becomes acidic and hypoxic. This triggers signaling cascades involving e.g. heterodimeric hypoxia-inducible factor (HIF). Activation of this hypoxia-induced transcriptional program is crucial for the tumor cell to survive its hostile microenvironment and its ability to metastasize. One of the genes HIF upregulated is carbonic anhydrase (CA)-IX (CAIX, gene G250/MN-encoded transmembrane protein). CA-IX catalyzes carbon dioxide (CO₂) thereby generating a proton (H⁺) and bicarbonate (HCO₃⁻), the latter of which is transported back into the cell and utilized to help safeguard intracellular pH (pHi) stability. Except for the stomach and the gallbladder, CA-IX expression is negligible in normal tissues. In contrast, a broad range of tumors express high levels of CA-IX, where the protein can serve as a biomarker for the early stages of tumor development but also as tumor marker of hypoxia associated with resistance to chemotherapy and radiotherapy. Preclinical and clinical studies have shown that CA-IX is a promising therapeutic target for detection and therapy for several cancer types. To date only a limited number of ant-CAIX monoclonal antibodies (mAbs) have been available for clinical testing as therapeutic and imaging agents. In the current study, we generated and functionally categorized a panel of 51 mouse mAbs that specifically bind to human CA-IX. Characterization of the mAbs revealed that of the mAbs with the best biophysical characteristics, three (3) mAbs are suitable as an antibody-drug conjugate (ADC), two (2) mAbs inhibit the CA-IX enzyme activity, and one (1) mAb that is suitable for CA-IX imaging purposes. These preliminary data presented here could thus form the basis for the development of novel CA-IX targeted immunotherapies and diagnostic tools for the treatment of cancer. Citation Format: Anne E. G. Lenferink, Jason Baardsnes, Traian Sulea, Cunle Wu, Maurizio Acchione, Maria L. Jaramillo, Paul C. McDonald, Francois Benard, Shoukat Dedhar. Identification and functional evaluation of monoclonal antibodies specifically targeting human Carbonic Anhydrase IX [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P038.