Development of a novel antibody-drug conjugate targeting both CEACAM5 and CEACAM6

Background: Carcinoembryonic antigen cell adhesion molecule (CEACAM) family members 5 and 6 are tumor-associated antigens frequently upregulated in epithelial cancers, including pancreatic ductal adenocarcinoma (PDAC) colorectal cancer (CRC), where they contribute to invasion, metastasis, survival, resistance chemotherapy, immune escape. CT109 is a novel antibody with dual specificity for both CEACAM5 6, mediated by binding shared glycoepitope. exhibits high affinity (in the single nM range) target. Recently CEACAM6 was identified as checkpoint. To further develop CT109, vitro vivo characterization of antibody-drug conjugate (ADC), CT109-SN-38, performed. Materials Methods: Immunoblots were performed against recombinant CEACAM5/6 lysates PDAC CRC lines assess CT109. Immunohistochemistry (IHC) also establish expression prevalence cancers confirm specificity. Internalization kinetics assessed pHrodo conjugation flow cytometry two lines. ADC IC50 values determined antigen-expressing line, BxPC-3, non-expressing PANC-1, using CellTiter Glo. Effects CT109-SN-38 heterotopic xenograft model nude mice that received triweekly injections three weeks. Results: binds surface immunoblots. remarkable IHC cores (3/3 cores). internalized antigen-expressing, but not non-expressing, cells half-maximal localization low pH compartments 24 hours. In vitro, auristatin conjugates exhibit robust killing cells. vivo, mediates specific tumor-killing, resulting reduced tumor volumes (through day 50, p < 0.001) burden below baseline subset (2/10 mice). Conclusions: anti-CEACAM5/6 antibody, proportion cores. However, CEACAMs does compromise IHC, no observed staining normal tissues. While GPI-linked proteins canonically viewed slowly or non-internalizing antigens, nonetheless internalized. It dose-dependent cytotoxic effect an SN-38, monomethyl (MMA) F, MMAE conjugate. similarly reducing growth model, 2/10 exhibiting regression throughout study. Further preclinical clinical development warranted. Conflict interest: Ownership: Dr. Cohava Gelber has partial ownership shareholder Stromatis Pharma. Board Directors: co-chairperson founder