A Highly Selective Humanized DDR1 Mab Reverses Immune Exclusion by Disrupting Collagen Fiber Alignment in Breast Cancer

Authors

Junquan Liu
Huai-Chin Chiang
Wei Xiong
Victor Laurent
Samuel C Griffiths
Jasmin Dülfer
Hui Deng
Xiujie Sun
Y Whitney Yin
Wenliang Li
Laurent P Audoly
Zhiqiang An
Thomas Schürpf
Rong Li
Ningyan Zhang

Publication Date

6-1-2023

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment 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 therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding epitope of PRTH-101 from the crystal structure of the complex between DDR1 extracellular domain (ECD) and the PRTH-101 Fab fragment with 3.15 Å resolution. We revealed the underlying mechanisms of action of PRTH-101 using both cell culture assays and

RESULTS: PRTH-101 has subnanomolar affinity to DDR1 and potent antitumor efficacy similar to the parental rabbit mAb after humanization. Structural information illustrated that PRTH-101 interacts with the discoidin (DS)-like domain, but not the collagen-binding DS domain of DDR1. Mechanistically, we showed that PRTH-101 inhibited DDR1 phosphorylation, decreased collagen-mediated cell attachment, and significantly blocked DDR1 shedding from the cell surface. Treatment of tumor-bearing mice with PRTH-101

CONCLUSIONS: This study not only paves a pathway for the 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.

Keywords

Animals, Mice, Collagen, Discoidin Domain Receptor 1, Extracellular Matrix, Neoplasms, Receptor Protein-Tyrosine Kinases, Tumor Microenvironment, Antibodies, Monoclonal

Comments

PMID: 37328286