title: Preclinical evaluation of carcinoembryonic cell adhesion molecule (CEACAM) 6 as potential therapy target for pancreatic adenocarcinoma.
abstract: Despite the availability of new targeted therapies, ductal pancreatic adenocarcinoma continues to carry a poor prognosis. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)6 has been reported as a potential biomarker and therapy target for this malignancy. We have evaluated CEACAM6 as a potential therapy target, using an antibody-drug conjugate (ADC). Expression of CEACAM6 in pancreatic adenocarcinomas was determined using immunohistochemistry on tissue microarrays. The expression pattern in granulocytes and granulocytic precursors was measured by flow cytometry. Murine xenograft and non-human primate models served to evaluate efficacy and safety, respectively. Robust expression of CEACAM6 was found in > 90% of invasive pancreatic adenocarcinomas as well as in intraepithelial neoplastic lesions. In the granulocytic lineage, CEACAM6 was expressed at all stages of granulocytic maturation except for the early lineage-committed precursor cell. The anti-CEACAM6 ADC showed efficacy against established CEACAM6-expressing tumours. In non-human primates, antigen-dependent toxicity of the ADC consisted of dose-dependent and reversible depletion of granulocytes and their precursors. This was associated with preferential and rapid localization of the antibody in bone marrow, as determined by sequential in vivo PET imaging of the radiolabelled anti-CEACAM6. Localization of the radiolabelled tracer could be attenuated by predosing with unlabelled antibody confirming specific accumulation in this compartment. Based on the expression pattern in normal and malignant pancreatic tissues, efficacy against established tumours and limited and reversible bone marrow toxicity, we propose that CEACAM6 should be considered for an ADC-based therapy approach against pancreatic adenocarcinomas and possibly other CEACAM6-positive neoplasms.
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA, USA. lauras@gene.com
authors.forename: Laura A
authors.initials: LA
authors.lastname: Strickland
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Maria
authors.initials: M
authors.lastname: Romero
authors.forename: Susan
authors.initials: S
authors.lastname: Spencer
authors.forename: Rich
authors.initials: R
authors.lastname: Erickson
authors.forename: Julie
authors.initials: J
authors.lastname: Sutcliffe
authors.forename: Caroline
authors.initials: C
authors.lastname: Verbeke
authors.forename: Paul
authors.initials: P
authors.lastname: Polakis
authors.forename: Nicholas
authors.initials: N
authors.lastname: van Bruggen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen