Abstract B124: Preclinical development of a novel therapeutic antibody to treat pancreas and colorectal cancers

Abstract

Abstract NPC-1C is a chimeric monoclonal antibody being developed as a novel biological treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. NPC-1C appears to recognize an aberrantly expressed form of MUC5AC expressed specifically by human colon and pancreatic tumor tissues and cell lines. NPC-1C does not cross-react with normal human tissues (and with MUC5AC from other type of cancers), however, except for occasional, weak binding to certain GI tract tissues, which may indicate a pre-malignant state. In vitro, the NPC-1C antibody exhibits specific ADCC activity against human colon and pancreatic tumor cells, but not against control tumor cell lines. In vivo, the anti-tumor efficacy of NPC-1C was tested using preestablished subcutaneous human pancreatic tumor xenograft models. The data showed significant, and reproducible, anti-tumor action, including some complete tumor regressions. The clinical application for this antibody was bolstered by several examples of human tumor tissues were stained with biotin-conjugated NPC-1C which show a strong correlation of NPC-1C staining against pancreatic and colon tumors, with approximately 45% of tumors staining strongly positive. The staining pattern was typical of mucin expression, but also showed cytoplasmic and cell membrane staining. The pre-clinical toxicity profile of NPC-1C in normal BALB/c mice demonstrated little, if any, toxicity following single or multiple intravenous injections of 10 mg/kg, 50 mg/kg, or 100 mg/kg of clinical-grade NPC-1C antibody. Toxicity parameters measured include body weight, food consumption, complete blood analysis, serum chemistries, gross pathology, and microscopic histopathology. The bio-distribution of radio-labeled NPC-1C in mice with pre-established subcutaneous human tumors revealed specific accumulation of NPC-1C at the tumor site, with little or no binding or accumulation in several major organ systems. Finally, we studied the cytokine and antibody responses to NPC-1C in the pre-clinical mouse model. Although anti-NPC-1C antibodies were detected (as expected) in a time-dependent fashion, we did not detect changes in Type I (IL-2 or g-IFN) and Type II (IL-4 or IL-5) cytokines in response to up to 100 mg/kg of NPC-1C either 3 days or 14 days after intravenous administration. The pre-clinical development of NPC-1C indicates that it is safe and efficacious, and suggest that it should be well-tolerated and may have clinical activity in patients whose tumor expresses the altered MUC5AC epitope. The FDA has approved the Investigational New Drug (IND) application to initiate a Phase I clinical trial with NPC-1C for patients with advanced pancreatic and colorectal cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B124.