Tunable Multivalent Platform for Immune Recruitment to Lower Antigen Expressing Cancers

Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs ‐ bivalent small molecules containing an antibody‐binding domain (ABD) and a target‐binding domain (TBD)) direct immune‐mediated clearance of diseased cells. Anti‐cancer ARM function relies on high tumor antigen vale...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2023-02, Vol.62 (9), p.e202214659-n/a
Main Authors: Lake, Benjamin P. M., Wylie, Ryan G., Bařinka, Cyril, Rullo, Anthony F.
Format: Article
Language:English
Subjects:
Antibodies
Antibodies - chemistry
Antigens
Avidity
Binding
Cell Recognition
Copy number
Domains
Drug Design
Humans
Immune clearance
Immune response
Immunochemistry
Male
Occlusion
Phagocytosis
Polymers
Prostate cancer
Prostatic Neoplasms
Recruitment
Tumors
Valency
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Summary:Chemical immunotherapeutic strategies including Antibody Recruiting Molecules (ARMs ‐ bivalent small molecules containing an antibody‐binding domain (ABD) and a target‐binding domain (TBD)) direct immune‐mediated clearance of diseased cells. Anti‐cancer ARM function relies on high tumor antigen valency, limiting function against lower antigen expressing tumors. To address this limitation, we report a tunable multivalent immune recruitment (MIR) platform to amplify/stabilize antibody recruitment to cells with lower antigen valencies. An initial set of polymeric ARMs (pARMs) were synthesized and screened to evaluate ABD/TBD copy number, ratio, and steric occlusion on specific immune induction. Most pARMs demonstrated simultaneous high avidity binding to anti‐dinitrophenyl antibodies and prostate‐specific membrane antigens on prostate cancer. Optimized pARMs mediated enhanced anti‐cancer immune function against lower antigen expressing target cells compared to an analogous ARM. Bifunctional chemical immunotherapeutics allow endogenous immune components to identify and destroy diseased targets. Herein we introduce and optimize polymeric antibody recruiting molecules (pARMs) for simultaneous avidity enhanced binding to prostate cancer cells and anti‐dinitrophenyl antibodies. The tunability and avidity‐enhanced potency of pARMs allows for increased immune proximity induction as compared to a monomeric construct.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202214659