CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.
| Autor: | Cardenas KCA; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Enos CW; Eastern Virginia Medical School, Norfolk, Virginia, USA., Spear MR; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Austin DE; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Almofeez R; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Kortchak S; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Pincus L; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA., Guo HB; University of Georgia Cancer Center, Department of Biochemistry and Molecular Biology and the Complex Carbohydrate Research Center (CCRC), USA., Dolezal S; University of Georgia Cancer Center, Department of Biochemistry and Molecular Biology and the Complex Carbohydrate Research Center (CCRC), USA., Pierce JM; University of Georgia Cancer Center, Department of Biochemistry and Molecular Biology and the Complex Carbohydrate Research Center (CCRC), USA., Furth E; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA., Gineste C; Vaxxinity Inc, Merritt Island, Fl, USA., Kwon Y; Institute: Food and Drug Administration, CDER, MD, USA., Gelber C; Stromatis Pharma, 9501 Discovery Blvd Manassas, VA 20109, USA. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Current cancer drug targets [Curr Cancer Drug Targets] 2024; Vol. 24 (7), pp. 720-732. |
| DOI: | 10.2174/0115680096260614231115192343 |
| Abstrakt: | Background: CEACAM5 and CEACAM6 are glycosylphosphatidylinositol (GPI)- linked members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which are frequently upregulated in epithelial cancers where they contribute to invasion, metastasis, immune evasion, and resistance to anoikis. CT109 is a novel antibody with dual specificity to both CEACAM5 and 6. Objectives: In this study, we aimed to perform the preclinical characterization of CT109 and antibody- drug conjugate (ADCs) derivatives of CT109, focusing on CT109-SN-38. Methods: CT109's cognate epitope was characterized by scanning mutagenesis. CT109 specificity and internalization kinetics were assessed by immunoblot and flow cytometry, respectively. Cognate antigen expression prevalence in colorectal cancer and normal tissue arrays was determined by immunohistochemistry. CT109 conjugations were generated by the reaction of reduced CT109 cysteines with maleimide-functionalized payload linkers. In vitro cytotoxic activity of CT109 ADCs was characterized on antigen-positive and negative pancreatic ductal adenocarcinoma cell (PDAC) lines using a luminometric viability assay. In vivo efficacy of CT109-SN-38 was assessed on a PDAC tumor xenograft model at 10 and 25 mg/kg concentrations. Results: CT109 was shown to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5 + /CEACAM6 + double-positive PDAC line, BxPC-3, with a t Conclusion: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted. (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|