Abstract 317: Isolation of highly selective antibodies against claudin 18.2 for the treatment of solid tumors

Abstract

Monoclonal antibodies (MAbs) are a well-established treatment approach in oncology and other diseases. Nevertheless, many multipass membrane proteins are largely inaccessible as antibody targets due to their poor expression, membrane-dependent structure, small extracellular regions, and high sequence conservation between humans and rodents. Integral Molecular’s MPS Antibody Discovery platform specifically addresses each of these challenges. A key enabling feature of MPS is the use of chickens as an evolutionarily divergent host species for immunization, allowing a more robust immune response for targets that are highly conserved in mammals. We will present on antibodies isolated against challenging membrane protein targets in oncology including Claudin 18.2 (CLDN18.2).CLDN18.2 is a transmembrane adhesion protein undetectable in most adult healthy tissues but highly expressed in gastric, pancreatic, esophageal, and lung cancers. Antibody discovery efforts against this validated target are challenging due to the abundant expression of the splice isoform CLDN18.1 differing by only 8 amino acids in the extracellular domain. As part of the MPS platform, we used virus-like particles (Lipoparticles) to immunize chickens with a high concentration of native CLDN18.2 protein and obtain high-titer immune responses. This enabled us to generate and isolate a large and diverse collection of MAbs (48 unique clones) and select candidates for optimization. We present a panel of three highly specific, humanized CLDN18.2 MAbs with picomolar affinities that are superior to the clinical-stage benchmark. We will show in-depth profiling data for the MAb panel that were used for lead selection and de-risking clinical development. These data include biosensor binding kinetics, amino-acid resolution epitope mapping, and specificity testing against the Membrane Proteome Array (MPA) consisting of 6,000 membrane proteins. This panel of preclinical antibodies are being developed for therapeutic use in various formats, including bispecifics, antibody-drug conjugates, and CAR-T applications. Citation Format: Brad Screnci, Trevor Barnes, Kristen Shema, Rebecca Rimkunas, Shruthi Kannan, Tim Phillips, Carmen Navia, Charles Azuelos, Tom Charpentier, Jennifer Houtmann, Lisa Miller, Lewis J. Stafford, Benjamin J. Doranz, Joseph B. Rucker, Ross Chambers. Isolation of highly selective antibodies against claudin 18.2 for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 317.