Faculty, Staff and Student Publications

Publication Date

9-5-2022

Journal

Journal of Experimental Medicine

DOI

10.1084/jem.20220214

PMID

35881112

PMCID

PMC9428257

PubMedCentral® Posted Date

7-26-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.

Keywords

Animals, B-Cell Activating Factor, B-Cell Maturation Antigen, Lymphoma, Large B-Cell, Diffuse, Multiple Myeloma, Signal Transduction, Transmembrane Activator and CAML Interactor Protein, Tumor Necrosis Factor Ligand Superfamily Member 13

Published Open-Access

yes

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