Bispecific antibodies – engineered drugs that can bind to two different tumor antigens – inhibit cancer growth by hitting multiple targets at once. Now three Johns Hopkins research groups describe promising early evidence that designing bispecific agents to bind to tumor antigens and T cells simultaneously could provide a viable approach to creating standard immuno-oncology drug treatments.
A Hopkins team focused on p53, a known tumor suppressor gene that is inactivated in some cancers but has proven extremely difficult to reactivate with drugs. The Hopkins researchers designed a bispecific antibody that could target the mutant p53 protein without interfering with intact p53 in normal cells, they explained in the journal Science.
The bispecific antibody they designed has one arm that binds to a fragment of the mutated p53 protein and another arm that binds to a T cell. In mouse models of multiple myeloma, the bispecific antibody stimulated T cells to kill cancer cells with mutant p53, the researchers reported. That caused the tumors to shrink.
Even when the p53 target was present at “extremely low” levels on the surface of the tumor cells, the researchers wrote, the bispecific antibody was still able to activate T cells to fight the cancer.
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A second study, published in Science Immunology, turned a bispecific antibody against another carcinogenic mutant gene that was difficult to combat: RAS. Mutated RAS proteins are difficult targets for drugs because they are often expressed at low levels.
The researchers developed mutation-associated neoantigen-targeting antibodies (MANAbodies) and then inoculated them on a bispecific antibody that targets T cells. They tested the resulting bispecific antibody in human cell lines from patients with lung and pancreatic cancer, showing that it could destroy tumor cells with low levels of mutated RAS, while leaving cells with only normal RAS.
The study “shows that it is possible to generate bispecific antibodies that are highly specific,” the authors wrote, and “capable of inducing target cell killing at very low antigen densities.” In fact, they are already used to creating bispecific antibodies that target other cancer-causing proteins, they said.
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The third Hopkins team looked for cancer cells that drive certain leukemias and lymphomas, but without damaging normal T cells. So they designed bispecific antibodies to target one of the two specific regions likely to be present on malignant T cells, TRBV5-5 or TRBV12.
In patient cell lines and mouse models of leukemia and lymphoma, the bispecific antibodies targeted and killed the cancer-causing T cells without affecting healthy T cells, and the cancer decreased, the researchers reported in Science Translational Medicine.
All three bispecific approaches could provide alternatives to personalized immunotherapies, such as engineered CAR-T cells made up of the immune cells of individual patients. There is already one bispecific antibody on the market, Amgen’s Blincyto, approved for the treatment of some patients with B-cell precursor acute lymphoblastic leukemia (ALL). And there are more in clinical trials.
But bispecific antibodies pose a number of challenges that must be addressed before the three approaches proposed by the Hopkins researchers can make progress in cancer treatment, Jon Weidanz, Ph.D., of the University of Texas, noted in a accompanying editorial that has been published. in science.
First, these drugs are usually small molecules that are quickly removed from the bloodstream, requiring continuous delivery, Weidanz wrote. Adding elements to bispecific antibodies to improve half-life would make them bulkier, which could reduce their potency, he added.
The studies “provide a potential way to obtain ready-to-use protein-based immunotherapeutics for the treatment of cancers” with specific antigens or mutations, Weidanz wrote. “However, more work will be needed to address the issues raised by these three and other studies before this ambitious goal can be achieved.”