A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer
Introduction
Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment (TME) has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models.
Methods
To develop a DDR1-targeting mAb as a potential cancer therapy, we humanized mAb9 with a CDR grafting strategy. The humanized antibody named PRTH-101 is currently in preclinical development. We revealed the underlying mechanisms of action of PRTH-101 using both cell culture assays and in vivo study in a mouse tumor model.
Results
PRTH-101 has a sub-nanomolar affinity to DDR1 and a potent antitumor efficacy similar to the parental rabbit mAb after humanization. Mechanistically, we showed that PRTH-101 significantly blocked DDR1 shedding from the cell surface. Treatment of tumor-bearing mice with PRTH-101 in vivo disrupted collagen fiber alignment (a physical barrier) in the tumor extracellular matrix (ECM) and enhanced CD8+ T cell infiltration in tumors.
Conclusion
This study not only paves a pathway for development of PRTH-101 as a cancer therapeutic, but also sheds light on a new therapeutic strategy to modulate collagen alignment in the tumor ECM for enhancing antitumor immunity.