Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1.

Autor:	Ludwig SD; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Meksiriporn B; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biology, School of Science, King Mongkut's Institute of Technology Ladkrabang, Bangkok 10520, Thailand., Tan J; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Kureshi R; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Mishra A; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Kaeo KJ; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Zhu A; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Stavrakis G; Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA., Lee SJ; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Schodt DJ; Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA., Wester MJ; Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA., Kumar D; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Lidke KA; Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM 87131, USA., Cox AL; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Dooley HM; Department of Microbiology and Immunology, Institute of Marine and Environmental Technology (IMET), University of Maryland School of Medicine, Baltimore, MD 21201, USA., Nimmagadda S; Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA., Spangler JB; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: jamie.spangler@jhu.edu.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 May 16; Vol. 31 (5), pp. 904-919.e11. Date of Electronic Publication: 2024 Mar 27.
DOI:	10.1016/j.chembiol.2024.02.014
Abstrakt:	Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes. Competing Interests: Declaration of interests The authors have filed intellectual property covering the technologies described herein (patent number PCT/US2023/072013). (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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