LAUSR

Claudin 18.2 (CLDN18.2) is a member of the claudin family of proteins that are involved in the formation of tight junctions in epithelia and endothelia. In normal tissue, CLDN18.2 is expressed exclusively on gastric epithelial cells. CLDN18.2 expression is maintained during malignant transformation of gastric epithelia. In addition, it is aberrantly expressed in other tumor types, including esophageal, pancreatic, and lung adenocarcinomas. Thus, CLDN18.2 is considered to be an attractive tumor target antigen for antibody-based cancer immunotherapy. ASP2138 is an immunoglobulin G (IgG)-based, asymmetric 2+1 format, T-cell bispecific antibody comprising bivalent humanized anti-CLDN18.2 antigen-binding fragments and a monovalent anti-CD3 single-chain variable fragment. CD3 is a surface protein complex expressed on all T-cell populations and its clustering causes T-cell activation. Therefore, CD3 bispecific antibodies allow for simultaneous engagement with both CD3 and a tumor-associated antigen (TAA), resulting in retargeting of cytotoxic T cells specifically against TAA-positive tumor cells in a human leukocyte antigen-independent manner. ASP2138 is in development for the treatment of patients with CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma or pancreatic adenocarcinoma, and is being evaluated in an ongoing phase 1/1b clinical trial (NCT05365581). In this study, ASP2138 demonstrated selective binding to CLDN18.2 and CD3 without binding to other homologs and isoforms of CLDN18.2. Cytotoxicity and T-cell activation of ASP2138 were assessed using CLDN18.2-expressing tumor cells in combination with human peripheral blood mononuclear cells (PBMCs) as effector cells in a redirected T-cell cytotoxicity assay in vitro. ASP2138 showed cytotoxicity against CLDN18.2-expressing gastric or pancreatic cancer cells and increased interferon-gamma production and expression of T-cell activation markers. The cytotoxic activities were dependent on the effector cell to target cell ratio and CLDN18.2 expression on tumor cells. ASP2138 exhibited an antitumor effect on human CLDN18.2-expressing gastric cancer in a human PBMC-engrafted NOG mouse model in vivo. In summary, ASP2138 is expected to show a clinical effect through cytotoxicity against CLDN18.2-expressing tumor cells by T-cell activation that results from selective binding to CLDN18.2 and CD3. Citation Format: Taisuke Nakazawa, Hiroaki Tanaka, Aya Kikuchi, Rumana Rashid, Kendra N. Avery, Jing Qi, Alex Nisthal, Masashi Shimazaki, Kenna Shirasuna. ASP2138, a novel 2+1 format, claudin 18.2 x CD3 bispecific antibody, demonstrates selectivity and activity in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2962.