Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance targeted therapy response in non-small cell lung cancer
Introduction
Non-small cell lung cancer (NSCLC) is the leading cause of cancer associated deaths worldwide. Patients have few therapeutic options and disease progression is inevitable, underscoring the critical need for 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. Our prior work demonstrated that PCDH7 modulates the MAPK signaling pathway by synergizing with mutant KRAS or mutant EGFR to promote lung tumorigenesis. Depletion of Pcdh7 reduces lung tumor burden and prolongs survival in mouse models of high-grade NSCLC, demonstrating that this protein is an actionable therapeutic target.
Methods
To assess the efficacy of targeting PCDH7 in NSCLC, we identified and characterized high affinity anti-PCDH7 monoclonal antibodies (mAbs) by generating B cell monoclonal antibodies and by screening a human antibody phage display library. We performed functional screening with the goal of identifying antibody candidates with high specificity and affinity for the PCDH7 extracellular domain, and the ability to inhibit downstream MAPK pathway activation and cell viability in multiple LUAD cell lines. We also evaluated the anti-tumor efficacy in multiple mouse models and determined the engagement of immune effector function in an Fc-dependent manner.
Results
We identified a lead candidate (Rb-mAb7) that reduced tumor growth in multiple mouse models and sensitized KRAS-mutant xenografts to the MEK inhibitor trametinib. In an EGFR-mutant model of LUAD, mAb7 reduced tumorigenesis and sensitized EGFR mutant LUAD cells to the third generation TKI osimertinib. We showed that Rb-mAb7 had binding specificity to PCDH7, and that this antibody did not bind to other members of the δ-1 protocadherin family members or other structurally similar cadherins. Furthermore, we humanized Rb-mAb7 and the humanized mAb7-IgG1 exhibited antibody dependent cellular cytotoxicity (ADCC) and Fc-mediated immune effector killing of tumor cells in humanized mice.
Conclusion
Collectively, these studies demonstrate that PCDH7 blockade is a promising therapeutic strategy for lung adenocarcinoma. Our findings also 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.