CT109-SN-38, a Novel Antibody-drug Conjugate with Dual Specificity for CEACAM5 and 6, Elicits Potent Killing of Pancreatic Cancer Cells.

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. OBJECTIVE: 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 showed to bind a glycoepitope centered on N309. CT109 is internalized in the CEACAM5+/CEACAM6+ double-positive PDAC line, BxPC-3, with a t1/2 of 2.3 hours. CT109 ADCs elicit a dose and antigen-dependent cytotoxic effect, with CT109-SN-38 exhibiting an IC50 value of 21 nM in BxPC-3 cells. In a BxPC-3 tumor xenograft model, CT109-SN-38 reduced tumor growth and induced regression in 3/10 mice at 25 mg/kg concentration. CONCLUSIONS: These data suggest that further preclinical and clinical development of CT109-SN-38 is warranted.

The Utility of Forensic Anthropology in the Medical Examiner's Office.

Over the past few decades, the field of forensic anthropology has seen major advancements and experienced a considerable growth of professionals in medical examiner/coroner offices. Despite this expansion, misconceptions regarding the role and utility of the anthropologist in the medicolegal setting still exist. This article brings together practitioners employed full-time in four medical examiner's offices, with each practitioner providing a unique perspective and emphasis regarding their role as an anthropologist. Discussed is the history of the anthropology division in each office as well as the types of casework and ancillary duties completed by the anthropologists. Consistently, the anthropologists are involved in the search and recovery of human remains, managing long-term unidentified cases, facilitating disposition of unclaimed decedents, and developing mass disaster protocols for their respective agency. Also consistent across the four offices is the fact that the anthropologists receive far more consult requests for trauma evaluation of nonskeletonized cases than any other type of case.