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

Authors :
Ludwig SD
Meksiriporn B
Tan J
Kureshi R
Mishra A
Kaeo KJ
Zhu A
Stavrakis G
Lee SJ
Schodt DJ
Wester MJ
Kumar D
Lidke KA
Cox AL
Dooley HM
Nimmagadda S
Spangler JB
Source :
Cell chemical biology [Cell Chem Biol] 2024 May 16; Vol. 31 (5), pp. 904-919.e11. Date of Electronic Publication: 2024 Mar 27.
Publication Year :
2024

Abstract

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.<br />Competing Interests: Declaration of interests The authors have filed intellectual property covering the technologies described herein (patent number PCT/US2023/072013).<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
2451-9448
Volume :
31
Issue :
5
Database :
MEDLINE
Journal :
Cell chemical biology
Publication Type :
Academic Journal
Accession number :
38547863
Full Text :
https://doi.org/10.1016/j.chembiol.2024.02.014