Developing high-affinity decoy receptors to treat multiple myeloma and diffuse large B cell lymphoma

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.

Povetacicept, an Enhanced Dual APRIL/BAFF Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell–Related Autoimmune Diseases

“…Thus, while these molecules arguably neutralize BAFF sufficiently, their inefficient blockade of APRIL activity leaves clear room for improvement. Reports of affinity-enhanced soluble BCMA fusion proteins as an alternate approach to cotarget APRIL and BAFF were recently described and may be in preclinical development, though their structure and mutational burden have not yet been revealed (45,46). Povetacicept addresses the limitations of WT TACI-Fc by dramatically improving the affinity of TACI for both APRIL and BAFF (Figure 1), leading to functional neutralizing activity both in vitro (Figure 2) and in vivo (Figures 3-5).…”

Decoy Receptor Fine-tunes Cytokinin Signaling

“…The principle of DcRs counteracting the activity of canonical receptors is becoming a legitimate therapeutical strategy to treat virus infections and genetically encoded diseases including cancer and inflammatory diseases (Gershoni, 2008). The engineered decoy receptors were successfully used to neutralize the virus particles (Capon et al, 1989; Arimori et al, 2022) or apoptosis-inducing factors (Kariolis et al, 2014; Miao et al, 2022).…”

The BAFF-APRIL System in Cancer

“…sBCMA-Fc binds to BAFF and APRIL with high affinity, and thus overcomes failure of treatment caused by the downregulation of cell-surface BCMA. Miao and colleagues have recently developed an affinity-enhanced sBCMA-Fc fusion protein which has shown promising antitumor activity in both MM and DLBCL [ 246 ]. Notably, the fusion protein has demonstrated a favorable safety profile and target-specificity in non-human primates, bypassing the drug-related toxicities (cytokine storm, tissue damage, neuropathy, and ocular toxicity) of bi-specific antibodies, ADCs, and CAR-T cells.…”