Therapeutic Targeting of Protocadherin 7 in Lung Adenocarcinoma

Abstract

The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Pages 38-92 are misnumbered as pages 41-95.Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype and remains the leading cause of cancer associated deaths worldwide. Patients have few therapeutic options, and disease progression is inevitable, underscoring the critical need for the identification of new targets and therapeutic approaches to treat this disease. We identified a critical oncogenic role for PROTOCADHERIN 7 (PCDH7), a cell surface protein and member of the Cadherin superfamily in NSCLC. PCDH7 is frequently overexpressed in lung adenocarcinoma (LUAD) and associates with poor clinical outcome. Depletion of Pcdh7 reduces lung tumor burden and prolongs survival in mouse models of high-grade NSCLC, demonstrating that this cell surface protein is an actionable therapeutic target. Here we report the development and characterization of high affinity anti-PCDH7 monoclonal antibodies (mAbs) that inhibit downstream MAPK pathway activation and suppress tumor growth in multiple mouse models, including KRAS- and EGFR-mutant models. A lead mAb sensitized tumors to the FDA-approved MEK inhibitor Trametinib, the tyrosine kinase inhibitor Osimertinib, and the KRASG12C inhibitor Adagrasib. Moreover, a humanized mAb7 decreased tumor growth in an Fc-dependent manner and enhanced antibody dependent cell-mediated cytotoxicity and granzyme B production. These findings provide an important step towards the clinical development of PCDH7-targeting antibodies for the treatment of NSCLC and other tumor types with high PCDH7 expression