Putting the BITE on Melanoma

Highly efficient elimination of melanoma cells expressing melanoma-associated chondroitin sulfate proteoglycan (MCSP) by MCSP/CD3-bispecific chain antibody constructs: A 61.


An engineered antibody-like molecule that binds skin cancer cells to killer T cells, literally tying melanomas to the immune system, could provide a novel therapy for the disease, according to researchers at Micromet, a biotechnology company based in Bethesda, Md., and Munich, Germany. Melanomas are particularly sensitive to T-cell therapies, the researchers say, and their novel antibody construct could be a means of engaging some of the most effective cancer-killing cells in the immune system's arsenal.
These agents are new class of artificial antibodies - what Micromet researchers term a BiTE class (for bispecific T-cell engager) - that are T cell-recruiting antibodies. Essentially, the researchers have linked the binding regions of two specific antibodies together with a short peptide chain.
In this case, one antibody binds to an activating receptor on the surface of killer T cells, called CD3, and the other binds to a protein generally found on the surfaces of skin cancers, called melanoma-associated chondroitin sulfate proteoglycan (MCSP).
"Unlike regular monoclonal antibodies used in cancer therapies, BiTE antibodies can recruit killer T cells for redirected lysis of tumor cells," said Roman Kischel, M.D., director of immunotherapy at Micromet. "By this approach only cells expressing the antigen are attacked by T cells, and we can see target cell lysis at very low picomolar concentrations of BiTE antibodies."
When MCSP-BiTE binds to cancer cells, the cells become visible for any killer T cell passing by. "The T cell will briefly attach to the BiTE-decorated cancer cell and inject its deadly cocktail of killer proteins into the tumor cell," Dr. Kischel said. "This event gears up the T cell to produce more killer proteins and to go into melanoma serial killing mode."
According to Dr. Kischel, the BiTE antibodies do not require specific killer T cells, which may circumvent many limitations of T-cell therapies, such as the mechanisms that some tumors use to escape the immune system and defects in the ability of immune cells to recognize antigen, a frequent problem among cancer patients. Even on the cellular scale, BiTE antibodies are tiny, about a third of the size of conventional antibodies, which Micromet researchers believe may aid by improved tumor penetration in the effectiveness of the therapeutic.
Currently, Micromet researchers are studying similar antibodies specific for B-cell lymphomas in a Phase I trial. The MCSP-BiTE antibodies are now undergoing preclinical studies in cell cultures and animal models.