376P - Preclinical Evaluation of the Anti-CLDN18.2 Antibody, IMAB362, in Pancreatic Carcinoma

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Drug Development
Pancreatic Cancer
Presenter Corina Heinz
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors C. Heinz1, R. Mitnacht-Kraus2, M. Kreuzberg2, S. Wöll2, U. Sahin3, Ö. Türeci2
  • 1Ganymed Pharmaceuticals, AG, 55131 - Mainz/DE
  • 2Ganymed Pharmaceuticals, AG, Mainz/DE
  • 3Translational Oncology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz/DE

Abstract

Background

Claudin 18.2 (CLDN18.2) is a tight junction protein restricted to the gastric mucosa cells; however, in the context of malignant transformation CLDN18.2 can be found in tumors derived from organs that do not normally express CLDN18.2, such as the pancreas. IMAB362 is a first-in-development monoclonal antibody that specifically targets CLDN18.2-expressing tumor cells. The aims of this preclinical study were to examine CLDN18.2 expression in pancreatic cancer (PC) and to evaluate IMAB362 as a single agent or in combination with standard chemotherapy for the treatment of PC.

Methods

CLDN18.2 expression in normal and neoplastic pancreatic tissues from patients with PC was assessed by a validated, semi-quantitative, IHC assay. IMAB362 pharmacodynamics, including binding characteristics, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and IMAB362-induced antitumor activity, were assayed in vitro (human PC cell lines) and in vivo (PC xenograft mouse models).

Results

CLDN18.2 expression levels and patterns in normal and malignant pancreatic tissue were very different. Whereas CLDN18.2 was not observed in normal tissue, CLDN18.2 was expressed in about 50% of tested neoplastic pancreatic tissues and premalignant lesions. IMAB362 bound with high specificity and high affinity to CLDN18.2-positive (CLDN18.2+) PC cells. IMAB362-induced efficient lysis of CLDN18.2+ PC cells through ADCC. In vitro, pretreatment of human PC cells with chemotherapeutic agents resulted in CLDN18.2 stabilization and a higher epitope density, which led to an increase in IMAB362-induced ADCC. Repeated doses of IV IMAB362 in mice bearing CLDN18.2+ PC xenografts resulted in slowed tumor growth and survival benefit. In vitro studies and animal data showed the antitumor activity of IMAB362 to be further augmented by pretreatment with gemcitabine and gemcitabine plus oxaliplatin.

Conclusions

In these preclinical studies, IMAB362 induced cell death in CLDN18.2+ human PC cell lines and xenografted tumors, and demonstrated potential as a targeted treatment for PC, both as single agent and in combination with chemotherapy.

Clinical trial identification

Legal entity responsible for the study

Ganymed Pharmaceuticals AG, A company of Astellas Pharma, Inc

Funding

Ganymed Pharmaceuticals AG, A company of Astellas Pharma, Inc

Disclosure

C. Heinz: Employee of Ganymed Pharmaceuticals AG. In addition, Dr. Heinz has patents 33PCT 34PCT, and 36PCT issued. R. Mitnacht-Kraus: Employee of Ganymed Pharmaceuticals AG, a company of Astellas Pharma, Inc. In addition, Dr. Mitnacht-Kraus has a patent P-24PCT issued, a patent P-33PCT issued, a patent P-34PCT issued, and a patent P-36PCT issued. M. Kreuzberg, S. Wöll: Employee of Ganymed Pharamceuticals AG, a company of Astellas Pharma, Inc. U. Sahin: Stock option owner, ex-shareholder and cofounder of Ganymed Pharmaceuticals AG and Founder/CEO/shareholder of Biontech Holding outside the submitted work. Dr. Sahin has several patents issued to this work that have been acquired by Astellas. Ö. Türeci: Stock option owner, ex-shareholder, cofounder & CEO of Ganymed Pharmaceuticals AG, has received consultancy fees from Astellas, and has several patents issued to this work that have been acquired by Astellas.