Monoclonal antibodies targeting PCDH7 inhibit tumor growth and enhance immune responses in <i>KRAS</i>-mutant non-small cell lung cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42234744.
- Also identified by DOI 10.1126/sciadv.aeb0794.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
We identified an important oncogenic role for protocadherin 7 (PCDH7), a cell surface protein frequently overexpressed in lung adenocarcinoma and associated with poor clinical outcome. <i>Pcdh7</i> depletion reduces tumor burden and prolongs survival in <i>Kras<sup>LSL-G12D</sup></i>; <i>Tp53<sup>fl/fl</sup></i> mice. These findings nominate this cell surface protein as an actionable therapeutic target and highlight the therapeutic potential of PCDH7 inhibition for non-small cell lung cancer. We report the development and characterization of high-affinity anti-PCDH7 monoclonal antibodies (mAbs) that inhibit downstream mitogen-activated protein kinase (MAPK) pathway activation and suppress tumor growth in multiple mutant <i>KRAS</i>-driven models. A lead mAb (mAb7) sensitized tumors to the US Food and Drug Administration-approved MAPK kinase inhibitor trametinib and the KRAS<sup>G12C</sup> inhibitor adagrasib. A humanized mAb7-IgG1 (Hu-mAb7) exhibited antibody-dependent cellular cytotoxicity and Fc-mediated immune effector killing of tumor cells in vivo. Moreover, a murinized antibody (Ms-mAb7) improved antitumor immunity in a <i>Kras<sup>G12D</sup></i> syngeneic tumor model by enhancing infiltration and activation of cytotoxic immune cells. These findings provide an important advance in the clinical development of PCDH7-targeting antibodies for lung cancer treatment.