Abstract 2903: IMAB362, a novel first-in-class monoclonal antibody for treatment of pancreatic cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 2903
• Main Authors: Tuereci, Oezlem, Woell, Stefan, Jacobs, Stefan, Mitnacht-Kraus, Rita, Sahin, Ugur
• Format: Journal Article
• Language: English
• Published: 01.10.2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-2903

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most frequent subtype (>80%) of pancreatic cancer (PC) is characterized by a generally lethal progress within a short period of time after primary diagnosis. Despite high efforts, the treatment options are very limited and mainly of palliative nature. Therefore, we investigated whether IMAB362 might represent a potential treatment option in this patient population. IMAB362 is a highly potent and tumor-cell selective therapeutic antibody which is currently in clinical development in gastro-esophageal cancer (in phase II and IIb trials). IMAB362 is directed against the tight junction molecule CLDN18.2, a proliferation-promoting transmembrane protein, which is maintained during malignant transformation. Our previous studies demonstrated, that CLDN18.2 is expressed in >55% of patients with PDAC and frequently in metastases at considerable levels. To evaluate the anti-tumor activity of IMAB362 we performed in vitro and in vivo experiments on CLDN18.2 expressing PC cell lines. IMAB362 exerts its anti-tumor function by antibody-dependant cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ADCC was assessed in various cancer cell lines and peripheral blood mononuclear cells (PBMCs) at an E:T-ratio of 40:1 in the presence of IMAB362. The efficacy ranged from 67.1 ± 6.8 to 92.6 ± 5.5%. EC50 was determined between 23.4 ± 12.3 ng/ml and 5.7 ± 4.4 µg/ml. IMAB362's capacity to induce CDC was analyzed by incubation of various tumor cell lines with healthy human serum as source for complement. We observed a dose-dependent lysis with EC50 values ranging from 0.3 - 2.6 µg/ml. In vivo studies in PC tumor bearing nude mice showed that administration of repeated doses of IMAB362 tends to result in inhibition of tumor growth and prolonged survival. Also, the anti-tumor effect of IMAB362 was strictly dependent on the expression of its target CLDN18.2. These results demonstrate that IMAB362 has antitumoral activity in vitro and in vivo against PC cell lines and PC xenografts. Most promising, the efficacy was due to IMAB362's single agent activity only. Combinations with established chemotherapies (e.g. 5-FU, gemcitabine) might deliver a strong rationale for clinical testing of the highly selective monoclonal antibody drug in patients with PDAC. Results from further in vivo testing of IMAB362 combinations with established chemotherapies will be presented at the meeting. Citation Format: Oezlem Tuereci, Stefan Woell, Stefan Jacobs, Rita Mitnacht-Kraus, Ugur Sahin. IMAB362, a novel first-in-class monoclonal antibody for treatment of pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2903. doi:10.1158/1538-7445.AM2014-2903