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

Autor:	Liu J; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Chiang HC; Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA., Xiong W; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Laurent V; Evotec (France) SAS, Campus Curie, 195 route d'Espagne, 31036 Toulouse CEDEX, Toulouse, France., Griffiths SC; Evotec (UK) Ltd, Abingdon, UK., Dülfer J; Evotec SE, Manfred Eigen Campus, Hamburg, Germany., Deng H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Sun X; Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA., Yin YW; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA., Li W; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Audoly LP; Parthenon Therapeutics Inc, Boston, Massachusetts, USA., An Z; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA Zhiqiang.An@uth.tmc.edu Thomas.schuerpf@parthenontx.com rli69@gwu.edu Ningyan.Zhang@uth.tmc.edu., Schürpf T; Parthenon Therapeutics Inc, Boston, Massachusetts, USA Zhiqiang.An@uth.tmc.edu Thomas.schuerpf@parthenontx.com rli69@gwu.edu Ningyan.Zhang@uth.tmc.edu., Li R; Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA Zhiqiang.An@uth.tmc.edu Thomas.schuerpf@parthenontx.com rli69@gwu.edu Ningyan.Zhang@uth.tmc.edu., Zhang N; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA Zhiqiang.An@uth.tmc.edu Thomas.schuerpf@parthenontx.com rli69@gwu.edu Ningyan.Zhang@uth.tmc.edu.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Jun; Vol. 11 (6).
DOI:	10.1136/jitc-2023-006720
Abstrakt:	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 in vivo study in a mouse tumor model. 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 in vivo disrupted collagen fiber alignment (a physical barrier) in the tumor extracellular matrix (ECM) and enhanced CD8 + T cell infiltration in tumors. 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. Competing Interests: Competing interests: LPA and TS are former or current employees and shareholders of Parthenon Therapeutics. NZ, ZA, RL and HD are inventors on a patent application (UTSH.p0262US.P1 and UTFH.P0362WO) for anti-DDR1 monoclonal antibodies and received stock options from Parthenon Therapeutics through a licensing agreement with University of Texas Health Science Center (UTHealth) at Houston, Texas. NZ, ZA and HD are employees of UTHealth. RL and ZA serve as a member on the Scientific Advisory Board of Parthenon Therapeutics and receive financial compensation for the advisory role. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu