Bispecific antibodies – drugs designed to bind to two different tumor antigens – inhibit the growth of cancer by hitting several targets at the same time. Now, three Johns Hopkins research groups describe promising early evidence that the design of bispecifics so that they bind simultaneously to tumor antigens and T cells could provide a viable approach to creating immuno-oncological drug treatments.
A Hopkins team removed p53, a well-known tumor suppression gene that becomes inactivated in some cancers, but has been shown to be extremely difficult to reactivate with medication. Hopkins researchers designed a bispecific antibody that could target the p53 mutant protein without interfering with intact p53 in normal cells, they explained in the journal Science.
The bispecific antibody they designed has an arm that attaches to a fragment of the mutant p53 protein and another that binds to a T cell. In multiple myeloma models in mice, the bispecific antibody stimulated T cells to destroy cancer cells. carrying the p53 mutant, the researchers reported. This caused the tumors to shrink.
Even when the p53 target was present at “extremely low” levels on the surface of tumor cells, the researchers wrote, the bispecific antibody was still able to activate T cells to fight cancer.
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A second study, published in Science Immunology, turned a bispecific antibody against another mutant gene that leads to cancer, which was difficult to target: RAS. Mutant RAS proteins are difficult drug targets because they are often expressed at low levels.
The researchers developed antibodies associated with the neoantigen-directed mutation (MANAbodies) and then grafted them onto a bispecific antibody that binds T cells. tumor cells with low levels of mutant RAS, leaving at the same time cells with normal RAS.
The study “shows that it is possible to generate bispecific antibodies that are very specific,” the authors wrote, and “capable of inducing the killing of target cells at very low antigen densities.” In fact, they have already become accustomed to creating bispecific antibodies that target other proteins that lead to cancer, they said.
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The third Hopkins team aimed to target cancer T cells that lead to certain leukemias and lymphomas – but to do so without affecting normal T cells. Thus, they designed bispecific antibodies to target either of the two specific regions that are likely to be present on malignant T cells, TRBV5-5 or TRBV12.
In patient cell lines and mouse models of leukemia and lymphoma, bispecific antibodies targeted and killed cancer-causing T cells without affecting healthy T cells, and the cancer regressed, the researchers in Science Translational Medicine reported.
All three bispecific approaches could offer alternatives to personalized immunotherapies, such as CAR-T cells constructed from the immune cells of individual patients. There is already a bispecific antibody on the market, Amgen’s Blincyto, approved to treat some patients with acute B-cell lymphoblastic leukemia (ALL). And more are in clinical trials.
But bispecific antibodies present some challenges that will need to be addressed before the three approaches proposed by Hopkins researchers can advance cancer treatment, said Jon Weidanz, Ph.D., of the University of Texas, in an accompanying editorial published in Science .
First, these drugs tend to be small molecules, which are rapidly cleared from the bloodstream, making it necessary to continue their administration, Weidanz wrote. Adding elements to bispecific antibodies to improve their half-life would make them more voluminous, which could diminish their potency, he added.
“Studies offer a potential pathway for conducting off-the-shelf immunotherapeutic-based proteins to treat cancers with specific antigens or mutations,” Weidanz wrote. “However, more work will be needed to address the issues raised by these three studies and others before this ambitious goal can be achieved.”