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

• DOI: 10.1136/jitc-2023-006720
• Publication Date: 2023-06-16T17:34:50Z
• 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
• Keywords: Mice; Discoidin Domain Receptor 1; Neoplasms; Tumor Microenvironment; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Animals; Receptor Protein-Tyrosine Kinases; Antibodies, Monoclonal; Basic Tumor Immunology; Collagen; RC254-282; 3. Good health; Extracellular Matrix

BackgroundImmune 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.MethodsTo 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 andin vivostudy in a mouse tumor model.ResultsPRTH-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-101in vivodisrupted collagen fiber alignment (a physical barrier) in the tumor extracellular matrix (ECM) and enhanced CD8+T cell infiltration in tumors.ConclusionsThis 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.