Abstract 7339: A highly efficacious next-generation CEACAM5 (CEA)-targeted Boltbody™ ISAC for the treatment of colorectal, pancreatic and lung tumors

Abstract Background: CEACAM5 is a well-characterized cell-surface antigen highly expressed on multiple solid tumors, particularly colorectal, pancreatic, and non-small cell lung cancers. Despite its favorable properties as a cancer target, no therapies targeting CEA have been approved to date. We are developing a novel class of molecules, Immune-Stimulating Antibody Conjugates (ISACs) with next-generation TLR7/8 agonists to activate tumor-infiltrating myeloid cells and initiate a broad innate and adaptive anti-tumor immune response.[1] Methods: A panel of anti-CEACAM5 antibodies was tested for binding affinity and specificity; CEACAM5-mediated antibody-dependent cellular phagocytosis (ADCP) by myeloid cells; and myeloid-mediated tumor cell killing. A subset of the antibodies was chemically conjugated to a proprietary next-generation TLR7/8 agonist and assessed in myeloid cell activation assays in vitro and tumor growth inhibition in vivo. Results: Our lead CEA-targeted ISAC binds with high affinity and selectivity to CEACAM5+ cell lines and tumors. In vitro, ISAC binding to tumor cells drives efficient ADCP by myeloid cells and stimulates production of critical immune-activating cytokines including IL-12p70, IFNγ, and TNFα. The next-generation TLR7/8 agonist payload is active in mice where it inhibits the growth of CEACAM5+ xenograft tumors in immune-compromised mice. In CEACAM5 transgenic mice, treatment with the CEA-targeted ISAC results in complete tumor regression of CEACAM5+ syngeneic tumors including models with low CEACAM5 expression. Failure of CEACAM5+ cell lines and CEACAM5-parental cell lines to form tumors upon rechallenge demonstrates development of immunological memory and epitope spreading during initial treatment. In cynomolgus monkeys the CEA-targeted ISAC was well-tolerated with no significant drug-related adverse events up to 15 mg/kg, the highest dose tested. Conclusions: This pre-clinical data set demonstrates the antigen-dependent induction of a robust innate and adaptive immune response by a next-generation CEA-targeted ISAC and the potential to treat CEACAM5+ human cancers. References: [1] Ackerman S, Pearson C, Gregorio J. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer 2021; 2: 18-33. https://doi.org/10.1038/s43018-020-00136-x Citation Format: Rishali Gadkari, Andrew Luo, David T. Omstead, Jess L. Nolin, JingJing Li, Chi-Ling Fu, Cecelia I. Pearson, Cindy Kreder, Karla Henning, Matthew N. Zhou, Stefan Chun, Shahid Khan, Romas Kudirka, Han Kim, Robert Veneziale, Lu Xu, William G. Mallet, Shelley E. Ackerman, Michael N. Alonso, Paul Ponath. A highly efficacious next-generation CEACAM5 (CEA)-targeted Boltbody™ ISAC for the treatment of colorectal, pancreatic and lung tumors [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 7339.