July 27, 2022 -- A soluble version of B-cell maturation antigen (BCMA), a B-cell surface receptor, may act as a decoy to stop two proteins driving the growth of blood cancers, according to a new study by researchers at Stanford University.
Writing in an article published July 26 in the Journal of Experimental Medicine, the researchers describe how a mutant version of BCMA bound to proteins -- a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) -- inhibit the growth of multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) in mice.
The protein binding, which was also seen in cynomolgus monkeys, suggests the mutant soluble BCMA may provide an additional treatment option for patients with MM and DLBCL, who today have five-year survival rates of less than 60%.
MM and DLBCL, which are among the most common hematological cancers, develop from antibody-producing B cells. Chemotherapy cytotoxic drugs are initially effective in many cancer patients, but relapses remain a problem. Approvals of chimeric antigen receptor (CAR) T-cell therapies have provided a new option for patients failed by conventional drugs, but while complete remissions are possible, toxicities limit eligibility and relapses still happen.
Researchers at Stanford identified the cell signaling proteins APRIL and BAFF as a way to expand the treatment options for patients with MM and DLBCL. The proteins control the development of normal B cells by binding to various cell surface receptors. However, when elevated the proteins can promote the growth and survival of malignant B cells.
Because BCMA binds strongly to both proteins, the researchers speculated the receptor could serve as a decoy and inhibit the development of MM and DLBCL. Soluble BCMA bound to APRIL to inhibit MM in mice but failed to stop BAFF from driving the growth of DLBCL. In response, the researchers engineered a mutant soluble form of BCMA that bound strongly to both proteins and thereby inhibited MM and DLBCL growth in mice.
The team then studied the mutant receptor, serum B-cell maturation antigen (sBCMA)-Fc V3, in cynomolgus monkeys, revealing that it reduced the activity of APRIL and BAFF without causing significant side effects and offering encouragement that the candidate has a future in humans in a range of indications.
"Collectively, our data support sBCMA-Fc V3 as a clinically viable candidate for the treatment of MM and DLBCL," said Dr. Yu Rebecca Miao, an instructor in the department of radiation oncology at Stanford University, in a statement. "The biological functions of BAFF and APRIL are not limited to B-cell malignancies but extend to autoimmune disorders and other diseases triggered by pathological B cells, suggesting an even broader clinical indication for sBCMA-Fc V3."