Highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer

Discoidin domain-containing receptor 1 (DDR1) plays an important role in cancer progression. However, the DDR1 function in tumors is still elusive. We recently reported that DDR1 promoted collagen fiber alignment and formation of a physical barrier, which causes immune exclusion from tumors. We also demonstrated that our DDR1 ECD-targeting mAbs can disrupt collagen fiber alignment and increase T Cell infiltration in tumors. In this study, we humanized a DDR1 ECD-targeting mAb and showed significant antitumor efficacy in an immunocompetent mouse model. We determined the binding epitope using gene mutagenesis, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and X-ray crystallography. Mechanistically, we showed that the humanized mAb inhibited DDR1 phosphorylation and, more importantly, blocked DDR1 shedding and disrupted a physical barrier formed by collagen fiber alignment in tumors. This study not only paves a pathway for development of PRTH-101 as a cancer therapeutic, but also broaden our understanding of the roles of DDR1 in modulation of collagen alignments in tumor extracellular matrix and tumor immune microenvironment.