378P - Preclinical characterization of IMAB362 for the treatment of gastric carcinoma

Abstract

Background: Monoclonal antibodies (mAbs) are a key component of cancer therapy. An ideal therapeutic mAb would selectively bind to cancer cells while avoiding binding to healthy tissue. In normal tissue, Claudin 18.2 (CLDN18.2) is expressed in gastric mucosal cell tight junctions, largely inaccessible to mAbs. Upon malignant transformation, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 making it targetable by mAbs. This has driven the development of an anti-CLDN18.2 mAb, IMAB362, which specifically targets CLDN18.2-positive cancer cells while sparing normal tissue. The preclinical characterization of IMAB362 as a targeted therapy for gastric cancer (GC) is presented here. Methods: CLDN18.2 expression was characterized in primary tumors and metastases (32 of which corresponded to primary tumors) from GC patients using a validated, semi-quantitative, IHC assay. IMAB362 binding characteristics and mechanism of action were assessed in vitro using CLDN18.2-expressing cell lines and in vivo in mouse tumor xenografts. Antitumor activity of IMAB362 was assessed in human GC cell line xenografts in mice treated with chemotherapy with/without IMAB362. Results: In patient-derived GC tissue, CLDN18.2 was frequently (∼80%) and robustly expressed in both primary and metastatic tumors. IMAB362 was highly selective for CLDN18.2 both in vivo and in vitro. IMAB362 mediated effective and target-selective antibody-dependent cellular cytotoxicity (ADCC) against GC cell lines with endogenous CLDN18.2 expression and induced complement-dependent cytotoxicity (CDC)-mediated lysis of CLDN18.2-expressing tumor cells. IMAB362-mediated ADCC and CDC were not affected by the presence of CLDN18.2-negative cancer cells. Treatment with chemotherapy sensitized tumor cell lines to IMAB362-mediated mechanisms by increasing CLDN18.2 expression; improved antitumor activity was observed in xenografted mice treated with IMAB362 + chemotherapy compared with mice treated with chemotherapy alone. Conclusions: IMAB362 is a target-selective mAb with strong immune effector mediated antitumor activity (ADCC, CDC) that contributes to the elimination of CLDN18.2-expressing GC cells and synergizes with chemotherapy. Legal entity responsible for the study: Ganymed Pharmaceuticals AG, A company of Astellas Pharma, Inc A company of Astellas Pharma Inc Ganymed Pharmaceuticals GmbH A company of Astellas Pharma Inc Ganymed Pharmaceuticals GmbH A company of Astellas Pharma Inc Ganymed Pharmaceuticals AG, A company of Astellas Pharma Inc Funding: Ganymed Pharmaceuticals AG, A company of Astellas Pharma, Inc A company of Astellas Pharma Inc Ganymed Pharmaceuticals AG, A company of Astellas Pharma, Inc Disclosure: 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: Employee of Ganymed Pharamceuticals AG, a company of Astellas Pharma, Inc. M. Utsch: Employee of Ganymed Pharmaceuticals AG, a company of Astellas Pharma, Inc. In addition, Dr. Utsch has a patent PCT/EP2012/002210 issued. 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.