Abstract 2675: A new dual-targeting anti-immune checkpoint therapeutic approach for the treatment of “hot” and “cold” tumors

Abstract Anti-Immune Checkpoint (ICP) antibody approaches provided a major breakthrough in the field of cancer therapy. However, their efficiency is mainly restricted to patients with “hot” tumors characteristics, which limits the breadth of their use. To tackle this limit, we developed a new strategy aimed at amplifying anti-ICP antibody ability to activate immune cells. This approach is based on antibodies engineered to make them able to target both an ICP receptor and a co-receptor often involved in receptor-mediated activation, namely Heparan Sulfate Proteoglycan. The dually-targeting engineered anti-ICP antibodies were produced in eukaryotic cells. They were purified to homogeneity using two chromatographic steps and remain stable for months in frozen conditions. A first engineered antibody-derived construct was assessed for its ability to impact immune cell activation and tumor-growth. It is able to stimulate subsets of immune cells from mouse splenocytes as well as from human peripheral mononuclear cells, in vitro. In addition, its injection in healthy mice triggers activation of T-cells. Last, in mice previously implanted with different types of cancer cells it impacts growth of “hot” as well as “cold” tumors. Immune profiling in a “cold” cancer model shows that the treatment decreases the proportion of MDSCs and increase that of CD8+ T-cells and NK-cells in tumor microenvironment making it close of that found in “hot” tumors. Altogether, our data indicate that our first engineered antibody-derived construct presents an attractive immunotherapeutic potential for a large variety of cancers paving the way for its evaluation in clinical phases. Citation Format: Moutuaata M. Moutuou, Nora DeLuce, Elodie Creton, Honorine Lucchi, Julien Accolas, Alexandra Savatier, Michel Léonetti. A new dual-targeting anti-immune checkpoint therapeutic approach for the treatment of “hot” and “cold” tumors 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 (6Suppl): Abstract nr 2675.