CYT-338 Shows Anticancer Activity in Preclinical Tests
CYT-338, an investigational myeloma therapy designed to simultaneously bind to cancer cells and activate immune cells called natural killer cells, has shown promising anti-cancer activity in preclinical studies.
A team led by scientists at Cytovia Therapeutics, the company developing CYT-338, will present the findings in a poster this month at the European Hematology Association’s 2022 Hybrid Congress, taking place both online and in Vienna, Austria, June 9–12. The poster is titled, “Novel Multifunctional Tetravalent CD38 NKp46 FLEX-NK Engagers Actively Target and Kill Multiple Myeloma Cells.”
CYT-338 is an antibody-like molecule that is designed to bind to two targets simultaneously. Part of the construct targets CD38, a molecule that is commonly expressed on myeloma cells. Other CD38-targeting medicines  already are approved to treat myeloma, such as Darzalex (daratumumab), sold by Janssen Pharmaceuticals.
The other part of CYT-338 binds to NKp46, a protein on the surface of natural killer cells (NK cells). As their name implies, NKs are able to kill other cells, including cancer cells. By binding NKp46, CYT-338 is designed to activate the cell-killing ability of these immune cells.
The researchers demonstrated that CYT-338 binds to CD38 on myeloma cell lines, and cannot bind to the cells if they are engineered to lack CD38. Notably, CYT-338 bound to CD38 with an intensity about twice that of Darzalex, and had more powerful NK-stimulating activity than Darzalex in cell experiments.
The researchers also conducted experiments in which they altered a small portion of the CD38 protein that is known to be important for Darzalex binding. This alteration interfered with Darzalex binding as expected, but it did not alter CYT-338 binding, suggesting that CYT-338 binds to the protein at a different site than Darzalex.
The scientists conducted preliminary tests of CYT-338, given in conjunction with NK cells purified from healthy donor blood, using mouse models of multiple myeloma. Results showed this treatment significantly inhibited tumor growth.
Notably, in these models treatment with Darzalex led to a marked reduction in levels of NK cells and also of another type of immune cell called monocytes. Darzalex also substantially induced NK cell fratricide — when one NK cell kills another NK cell — and led to a powerful release of cytokines, pro-inflammatory molecules often associated with treatment side effects.
By contrast, CYT-338 did not significantly lower immune cell counts or induce cytokine release, and NK cell fratricide was substantially lower than with Darzalex.
“These results suggest that the CYT-338 engager has a favorable NK cell engager profile for targeting CD38 expressing multiple myeloma distinct from daratumumab,” the researchers concluded.
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