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Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Posted: Monday, December 5, 2022
A research team including Yu Rebecca Miao, PhD, of Stanford University, California, have engineered a mutant soluble B-cell maturation antigen (BCMA) that has a high binding affinity with the proliferation inducing ligand (APRIL), which regulates B-cell maturation and differentiation. The research, published in the Journal of Experimental Medicine, showed that the decoy BCMA (sBCMA-Fc V3) was able to inhibit the growth of multiple myeloma tumors in mouse models while exhibiting a favorable toxicity profile in nonhuman primates.
The researchers used INA-6 and MM1.R cell lines to validate the dependence of multiple myeloma growth on BCMA signaling and by using Tet-off doxycycline (dox)-controlled BCMA-stable knockdown system (dox shBCMA) to inhibit multiple myeloma tumor growth in mice. They also found a significant reduction in the level of human myeloma immunoglobulin protein secreted by tumors in mice treated with shBCMA.
Next, in vitro cytotoxicity assays were performed to test the toxicity of the wild-type soluble BCMA decoy receptor sBCMA-Fc. Multiple myeloma cell survival decreased as concentrations of sBCMA-Fc increased, corroborating the instigative role of APRIL in multiple myeloma growth. Subsequent treatment with sBCMA-Fc in mice engrafted with human multiple myeloma cells showed a significant reduction in tumor growth as well as increased overall survival.
Finally, the researchers engineered an affinity-enhanced sBCMA-Fc V3 and tested its antitumor activity against wild-type sBCMA-Fc at various doses. The sBCMA-Fc V3–treated group had a significant improvement in antitumor activity compared with the wild-type at lower doses, according to the study authors, and no difference at a higher dose of 10 mg/kg.
“Here, we provide new insight into the global translational landscape of multiple myeloma cells upon the loss of BCMA and identify a distinct subgroup of proteins that are translationally controlled, which otherwise would not be detected by measuring changes in total mRNA transcripts,” the researchers concluded.
Disclosure: For full disclosures of the study authors, visit rupress.org.
Journal of Experimental Medicine
