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.

Differential Effects of Predosing on Tumor and Tissue Uptake of an111In-Labeled Anti-TENB2 Antibody–Drug Conjugate

“…For example, predosing is used in approved radioimmunotherapy approaches using both 90 Y-ibritumomab tiuxetan (Zevalin; Bayer Schering Pharma AG) and 131 I-tositumomab (Bexxar; GlaxoSmithKline) and has become standard practice in radioimmunotherapy targeting the CD20 antigen (30,31). However, few examples exist for translation of such dosing strategies for ADCs (32). Predosing has been explored in the clinical imaging of ovarian carcinomas (33) and was also shown to decrease spleen uptake in imaging of non-Hodgkin lymphoma patients (34).…”

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

“…Considerable effort has gone into making cyclotronproduced Cu-64 (half-life, 12.7 h, very similar to I-123) available in the USA (67): It has been applied to imaging the biodistribution and tissue kinetics of several antibodies in non-human primates including trace doses of anti-CEACAM-6 (68). Despite the excellent image quality at time points up to 24 h, the duration of the Cu-64 studies was limited to 3 days at most, constrained by the half-life.…”

Theranostics Using Antibodies and Antibody-Related Therapeutics

“…In 1 study, 3 doses of 89 Zr-labeled naked antibody were evaluated as part of an ADC targeting mesothelin in mice bearing human pancreatic tumor xenografts. Tumor uptake decreased with increasing doses of the naked mAb (38), indicating dose-dependent and saturable tracer distribution at doses of 25 and 100 mg in mice. Biodistribution and tumor uptake were also investigated with an 89 Zr-labeled antimesothelin naked antibody in patients subsequently treated with a mesothelin-directed ADC (41).…”

“…The results showed uptake of the radiolabeled naked antibody in pancreatic and ovarian tumors. Strickland et al administered a carcinoembryonic cell adhesion molecule 6-directed ADC to monkeys and assessed biodistribution with a 64 Cu-labeled anti-carcinoembryonic cell adhesion molecule 6 naked mAb (38). The highest tracer uptake was seen in the bone marrow.…”

“…Naked antibody uptake is assumed to reflect ADC uptake and thus may predict whether a patient will respond to ADC therapy. This approach was used in 3 preclinical trials in mice and 1 study in both mice and nonhuman primates (37)(38)(39)(40). Organ biodistribution and tracer tumor uptake were assessed.…”