One CD38 inhibitor, or blocker, is approved by the U.S. Food and Drug Administration (FDA) to treat multiple myeloma, and several others are currently being tested in clinical trials.
How do CD38 inhibitors work?
CD38 is a protein that is primarily found on the surface of multiple myeloma cells. Other cells carry CD38, including red blood cells, although at lower levels. The protein’s strong association with multiple myeloma cells is what makes CD38 a treatment target.
CD38 inhibitors are antibodies, which are produced by the immune system to recognize and eliminate harmful invaders such as viruses and bacteria. They bind specifically to one part of a particular protein. CD38 inhibitors are synthetic antibodies designed to bind to the CD38 protein. When they bind to CD38 on myeloma cells, they block the cells’ growth and induce their death.
FDA-approved CD38 inhibitors
Darzalex (daratumumab), marketed by Janssen, is an FDA-approved CD38 inhibitor that may be used as a monotherapy in multiple myeloma patients who already tried at least three other therapies, including a proteasome inhibitor and an immunomodulatory agent.
Darzalex is also approved to be used in combination with other medications, such as Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone, by select groups of multiple myeloma patients. Information on specific combinations in distinct patient groups is available here.
CD38 inhibitors in clinical trials
Isatuximab, developed by Sanofi, targets a particular region on the CD38 protein to trigger apoptosis (programmed cell death) and an immune response. It has been granted orphan drug status as a potential multiple myeloma therapy by the FDA and the European Medicines Agency (EMA). A biologics license application requesting its approval for people with hard-to-treat (relapsed/refractory) multiple myeloma is under FDA review with a decision expected around late April 2020.
Sorrento Therapeutics is developing chimeric antigen receptor T-cells (CAR-T cells) against CD38. CAR-T cells are engineered immune cells (T-cells) that specifically bind to one part of a particular protein. CAR-T CD38 cells are designed to bind to and selectively kill cells that have high levels of CD38 on their surface, such as myeloma cells. The therapy is currently in Phase 1 clinical trial (NCT03464916) in advanced multiple myeloma patients.
GBR 1342, being developed by Glenmark Pharmaceuticals, is a bispecific antibody against CD3 and CD38. CD3 is a protein found on the surface of T-cells. By binding to CD3, the antibody is thought to activate T-cells, directing them against CD38-producing cells. GBR 1342 has been named an orphan drug as a potential treatment for previously-treated multiple myeloma patients. Its safety and tolerability are now being evaluated in a Phase 1 clinical trial (NCT03309111).
TAK-079 is a CD38-binding antibody being developed by Takeda. It is currently being tested, in combination with standard-of-care therapy, in a Phase 1 clinical trial (NCT03984097) in newly diagnosed patients, and in Phase 1/2 trial (NCT03439280) in those with advanced multiple myeloma.
Takeda is also developing the toxic agent TAK-169, which is designed to internalize and kill CD38-positive cells by blocking protein synthesis. It is in a safety and early efficacy Phase 1 clinical trial (NCT04017130) in people with relapsed/refractory multiple myeloma.
Last updated: Nov. 11, 2019
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