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Background CEACAM5 (CEA) is a well-characterized tumor associated antigen frequently upregulated in tumors of epithelial origin including colorectal, pancreatic and lung. Several CEA-directed therapies have been evaluated clinically including antibodies, antibody-drug conjugates (ADC), and cell-based therapies, but none have been approved to date. We are developing a CEA-targeted therapy with a distinct mechanism of action based on our next-generation Immune-Stimulating Antibody Conjugate (ISAC) platform. 1 ISACs offer several key advantages over other treatment modalities. Tumor-specific targeting activates myeloid cells within the tumor microenvironment that can kill tumors cells directly and stimulates a more durable adaptive T-cell response with immunological memory with epitope spreading.Methods Our CEA-targeted ISAC was constructed by conjugation of a next-generation TLR7/8 immune-stimulating payload via a non-cleavable linker to a novel CEA mAb, P601. The new CEA ISAC is active in human, non-human primate and mouse systems and has several advantages over reference CEA antibodies such as tusamitamab and labetuzumab.Results Our novel CEA mAb, P601 binds with high affinity and selectivity to human and cynomolgus CEA+ cells. Unlike reference CEA Abs, soluble or shed CEA has minimal impact on P601 cell binding, even at high molar excess of antigen. P601 mediated antibody-dependent cellular phagocytosis (ADCP) and macrophage-mediated killing of CEA+ tumor cells that was superior to reference CEA antibodies. In addition, CEA ISACs with P601 as the antibody backbone stimulate greater cytokine production in human conventional DC (cDC) cocultures with CEA+ tumor cells than tusamitamab-based ISACs.Our next-generation CEA ISAC with P601 as the antibody backbone (CEA ISAC) is active in non-human primate PBMC co-cultures with CEA+ tumor cells and in mouse myeloid cell co-cultures. These features facilitate toxicology assessment in non-human primates and avoid the need for a surrogate payload in mouse models, respectively. In MC38-CEA syngeneic tumor models established in CEA transgenic mice, our CEA ISAC resulted in 100% complete responses at 5 mg/kg. Inhibition of tumor growth in cured mice rechallenged with MC38-CEA tumor cells demonstrated induction of immunological memory. The CEA ISAC compares favorably to other CEA-targeted modalities and inhibited tumor growth at lower doses than cytotoxic ADCs. Finally, in a non-GLP NHP toxicology study the next-generation CEA ISAC was well-tolerated with no significant drug-related adverse events observed up to 15 mg/kg, the highest dose tested.Conclusions These pre-clinical data demonstrate induction of a robust innate and adaptive immune response by our next-generation CEA-targeted ISAC and the potential to treat CEACAM5+ human cancers.Reference Ackerman SE, et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat Cancer 2021;2(1):18–33. doi: 10.1038/s43018-020-00136-x