Japanese researchers are proposing a whole new avenue for combating multiple myeloma (MM). Researchers at Osaka University reported in Nature Medicine that they have found a new target for a monoclonal antibody–based treatment for patients with MM.
They conducted a study to see if a cancer-specific antigen formed by the modification of proteins during or after synthesis, such as glycosylation or conformational changes, could open up a new treatment avenue. The team theorized new antigen epitopes could be discovered by thoroughly searching for cancer-specific monoclonal antibodies and characterizing the recognized antigens.
Study investigator Naoki Hosen and his colleagues applied this strategy to identify novel therapeutic targets for MM. The team screened more than 10,000 anti-MM monoclonal antibody clones and identified MMG49 as an MM-specific monoclonal antibody uniquely recognizing a subset of integrin β7, a cell-surface receptor that facilitates cell-extracellular matrix adhesion.
MMG49 reacted to MM cells, but not other bone marrow cell types in MM patient samples. For this investigation, the team used candidate monoclonal antibodies to stain bone marrow cells from patients with MM. They identified MMG49 as a candidate that exhibited distinct binding to MM cells but negligible binding to normal leukocytes or non-MM cells in 45 of 51 MM samples. This prompted the researchers to design a chimeric antigen receptor (CAR) that incorporates a fragment derived from MMG49. The resulting MMG49 CAR T-cell therapy was found to have anti-MM effects without damaging normal blood cells.
“We found that the activated integrin β7 serves as a specific target for CAR T-cell therapy against MM,” said Hosen. “It will be tested in a clinical trial in 2 years.”
The researchers demonstrated that elevated expression and constitutive activation of integrin β7 resulted in high MMG49 reactivity on MM cells. They also found that MMG49 binding was hardly detectable in other cell types and this included normal integrin β7 + lymphocytes. The researchers concluded that MMG49 CAR T-cell therapy appears promising and warrants further investigation.
“A structure of a wild-type protein in an activated state can serve as a target for cancer immunotherapy. Our findings suggest that cancer immunotherapeutic targets may yet be identified in many cell surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific,” Hosen told OncoTherapy Network.