Role of Novel B-Cell Surface Receptors in the Inhibition of Diffuse Large B-Cell Lymphoma

By: Emily Rhode
Posted: Monday, November 28, 2022

The cell signaling protein BAFF controls the development of normal B cells by binding to cell receptor proteins. However, elevated BAFF levels seem to encourage the production and treatment resistance of malignant B cells in diffuse large B-cell lymphoma (DLBCL), leading to disease progression and poor outcomes. Now, according to a study published in the Journal of Experimental Medicine, an engineered decoy B-cell maturation antigen (BCMA) that binds to BAFF may be a clinically viable candidate for the treatment of patients with B-cell malignancies. Yu Rebecca Miao, PhD, of Stanford University, California, and colleagues created a high-affinity, mutant version of soluble BCMA, named sBCMA-Fc V3, which blocked the growth of DLBCL in mice.

BAFF-sensitive SU-DHL-6 and Daudi DLBCL cells were treated with ascending concentrations of sBCMA-Fc to assess in vitro cytotoxicity. Then, mice with SU-DHL-6 tumors were dosed every 48 hours with 10 mg/kg of sBCMA-Fc. No significant antitumor benefit was found in the mouse models, leading the researchers to hypothesize that sBCMA-Fc lacks a great enough binding affinity to BAFF to reduce DLBCL growth.

The team went on to engineer sBCMA-Fc V3, an sBCMA mutant with a 500-fold improvement in BAFF binding affinity. In vivo mouse model assessment showed that sBCMA-Fc V3 significantly reduced DLBCL tumor size. Furthermore, a head-to-head study of sBCMA-Fc V3 and other known BAFF-inhibiting therapeutics revealed the engineered mutant resulted in the most robust antitumor activity, according to the investigators.

“More importantly,” the study authors concluded, “sBCMA-Fc V3 has a favorable safety profile and on-target mechanism of action in both murine and nonhuman primate models.”

Disclosure: For full disclosures of the study authors, visit rupress.org.

Journal of Experimental Medicine

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