Abstract 4792: Highly specific GLUT-1 inhibiting antibodies for the treatment of pancreatic cancer

Abstract Background: Cancer cells often exhibit upregulated glucose metabolism to support their abnormal growth and division. Targeting the cancer-specific glucose transporter GLUT-1 offers a promising strategy to limit glucose uptake and disrupt tumor metabolism. Unlike small molecule inhibitors, monoclonal antibodies provide a unique opportunity to selectively target complex multi-pass membrane transporters. This study presents the development of highly specific antibodies that recognize GLUT-1 glycovariants, effectively blocking GLUT-1 function in cancer cells while preserving glucose transport across the blood-brain barrier. Methods: GLUT-1-specific monoclonal antibodies were generated using GLUT-1-displaying virus-like particles (VLPs) as immunogens. Chickens were chosen for immunization due to their ability to produce antibodies against highly conserved multi-transmembrane proteins. Antibody discovery was conducted using HybriFree B cell cloning technology and phage display. Functional screens included assays for 2-deoxyglucose uptake inhibition and cancer cell proliferation. Results: The identified antibodies bind GLUT-1 with nanomolar EC50 values and exhibit no cross-reactivity with other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and reprograms GLUT-1-dependent cancer cells to rely on oxidative phosphorylation (OXPHOS). This metabolic shift synergizes with OXPHOS inhibitors, resulting in significant cancer cell growth inhibition at doses subtherapeutic as monotherapies. In vivo, the combination of ICO-33 and an OXPHOS inhibitor was well-tolerated and led to substantial tumor growth suppression in colorectal and pancreatic cancer models. Importantly, ICO-33 preserves glucose uptake in the brain, minimizing systemic toxicities. Conclusions: This study highlights the discovery of GLUT-1-targeting monoclonal antibodies with high specificity and efficacy. The lead antibody, ICO-33, effectively restricts glucose uptake in cancer cells and enhances sensitivity to OXPHOS inhibitors, demonstrating its potential as a candidate for clinical development in cancer therapy. Citation Format: Siret Tahk, Paule Hermet, Kyumhyuk Kim, Takefumi Morizumi, Anu Ustav, Kai Virumäe, Robin Pau, Korneelia Anton, Alastair J. King, Francisca Neethling, Andres Männik, Joan Teyra, Oliver Ernst, Mart Ustav. Highly specific GLUT-1 inhibiting antibodies for the treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4792.