Decoy Molecules Curb Blood Cancer Growth

Researchers at Stanford University have developed “decoy receptor” molecules that inhibit the growth of both multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL) in mice. In a study published recently in the Journal of Experimental Medicine, the authors also showed that the molecules were nontoxic in monkeys, suggesting they could be used to treat humans with these common blood cancers.

Both MM and DLBCL develop from the body’s antibody-producing B cells. The five-year survival rate for patients diagnosed with either of these diseases is less than 60%. In recent years, the use of genetically engineered CAR T cells to specifically kill cancerous B cells has been effective in some patients, but this immunotherapeutic approach often comes with significant side effects and is unsuitable for elderly patients. 

“Safe and effective targeted therapies are therefore still needed for patients who exhaust currently available treatment options,” says study author Dr. Yu Rebecca Miao, an instructor in the Department of Radiation Oncology at Stanford University.

Miao and colleagues suspected that two cell signaling proteins, APRIL and BAFF, could be effective therapeutic targets for MM and DLBCL. By binding to several different cell surface receptor proteins, APRIL and BAFF control the development of normal B cells. But elevated levels of APRIL and BAFF promote the growth and survival of malignant B cells, facilitating blood cancer progression and treatment resistance. In particular, APRIL is linked to the progression of MM, whereas BAFF is associated with DLBCL.

Miao and colleagues investigated whether a soluble version of BCMA—a B cell surface receptor that binds to both APRIL and BAFF—would act as a “decoy receptor” to mop up excess APRIL and BAFF and prevent these proteins from driving the growth of cancerous B cells.  

They found that soluble BCMA was able to bind to APRIL and inhibit the growth of MM in mice. However, the decoy receptor only bound weakly to BAFF and was therefore unable to reduce the growth of DLBCL. The team therefore engineered a mutant version of soluble BCMA that binds strongly to both APRIL and BAFF. This molecule, dubbed sBCMA-Fc V3, was able to impede the growth of both MM and DLBCL in rodents.

sBCMA-Fc V3 also reduced the activity of APRIL and BAFF in cynomolgus monkeys without causing any significant side effects.

“Collectively, our data support sBCMA-Fc V3 as a clinically viable candidate for the treatment of MM and DLBCL,” Miao says. “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.”