Abstract 3760: Local activation of immune cells and depletion of Tregs by tumor collagen-binding checkpoint immunotherapy

Abstract Checkpoint inhibitor immunotherapy has demonstrated limited efficacy in 'immunologically cold' tumors, necessitating innovative approaches to treat over 80% of CPI-unresponsive cancer patients. Our research developed a groundbreaking drug delivery strategy using tumor collagen-binding domain (CBD), derived from von Willebrand Factor A3 domain, recombinant fusion with checkpoint inhibitors to target tumors after intravenous injections.By engineering a novel CBD-anti-CTLA4 construct, we achieved precise tumor microenvironment targeting through the unique property of accumulating in tumor stroma's exposed collagen. This molecular engineering approach dramatically reduces systemic toxicity such as liver toxicity while enhancing anti-tumor efficacy of anti-CTLA4 antibody across multiple cancer types including breast cancer, glioblastoma, colon cancer, and melanoma models. The technology's strength is that after intravenous injection, we observe tumor as the primary site of drug accumulation.The specificity of localization within tumor tissues leads to minimizing off-target effects characteristic of traditional checkpoint inhibitors. CBD-anti-CTLA4 antibody demonstrates superior cancer treatment capabilities, including complete tumor regression in glioblastoma, previously unresponsive models. Very interestingly, CBD-anti-CTLA4 antibody can infiltrate into the tumors very deeply into the tissues although normal anti-CTLA4 antibody did not. Thus, we observed very efficient Treg depletion in the tumors, which normal anti-CTLA4 antibody could not do. Key translational achievements include developing a humanised version validated as safe in preclinical studies. This innovative drug delivery strategy to deep tumor tissues represents a significant advancement in antibody delivery, offering hope for more effective, targeted interventions in challenging tumor environments. Specifically, Treg depletion within the tumors will become more efficient by this technology, unlocking the full potential of anti-CTLA4 antibody. By reimagining checkpoint inhibitor delivery, we create potential pathways to overcome current limitations in cancer immunotherapy. Citation Format: Jun Ishihara. Local activation of immune cells and depletion of Tregs by tumor collagen-binding checkpoint immunotherapy [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 3760.