Abstract 1876: Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth

Abstract Background: Upregulated glucose metabolism is one of the strategies cancer cells use to fuel their abnormal cell growth and division. Targeting the cancer-specific glucose transporter GLUT-1 is a promising approach to restrict glucose uptake and challenge the metabolic needs of tumor cells. Antibodies, as opposed to small molecule inhibitors, are an attractive modality to therapeutically target complex muti-pass membrane transporters. Here we report the development of antibodies that very specifically block the function of only GLUT-1. Methods: Monoclonal antibodies against GLUT-1 were generated using virus-like particles. For immunization, chickens were used as they are evolutionarily distant from mammals and can produce antibodies with prolonged CDR3-s in VH, which could facilitate their binding to the limited extracellular region of GLUT-1. Antibody discovery was performed with HybriFree B cell cloning technology followed by functional screens with 2-deoxyglucose uptake interference or cell proliferation measurements. Results: The discovered antibodies specifically bind to GLUT-1 with low nanomolar EC50 values and do not target other glucose transporters. The lead candidate, ICO-33, inhibits glucose uptake and rewires the metabolism of GLUT-1-dependent cancer cells to rely on oxidative phosphorylation. This results in a significantly synergistic cancer proliferation inhibition with ICO-33 and OXPHOS inhibitor combinations in doses that do not inhibit proliferation as single agents. ICO-33 and OXPHOS inhibitor treatment is well-tolerated and demonstrates a drastic tumor growth inhibition in in vivo colorectal and pancreatic cancer models. Conclusions: We describe the discovery of highly specific monoclonal antibodies targeting GLUT-1. We further demonstrate that the restriction of the much-needed glucose uptake by ICO-33 makes cancer cells highly susceptible to OXPHOS inhibitor co-therapy both in vitro and in vivo, validating the antibody as a promising candidate for clinical development. Citation Format: Siret Tahk, Kai Virumae, Korneelia Anton, Paule Hermet, Robin Pau, Mario Plaas, Maiken Abel, Denis Belitškin, Luciano Galdieri, Steven Garner, Jillian Krings, Kaleb Collver, Emily Schultz, Kaitlyne Powers, Alastair King, Francisca Neethling, Anu Planken, Mart Ustav, Joan Terya, Andres Mannik, Mart Ustav. Development of therapeutic antibodies targeting the GLUT-1 transporter to restrict cancer cell growth [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 1876.