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Title: Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1
Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engage- ment 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, necessi- tating novel approaches to enhance performance. Here, we report the development of antibody fusion pro- teins 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 comple- mentary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell acti- vation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic anti- bodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.  more » « less
Award ID(s):
2143160
PAR ID:
10569107
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Corporate Creator(s):
Editor(s):
NA
Publisher / Repository:
PubMed
Date Published:
Journal Name:
Cell Chemical Biology
Volume:
31
Issue:
5
ISSN:
2451-9456
Page Range / eLocation ID:
904 to 919.e11
Subject(s) / Keyword(s):
N/A
Format(s):
Medium: X Size: N/A Other: N/A
Size(s):
N/A
Sponsoring Org:
National Science Foundation
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