Bispecific antibodies – manufactured drugs that can bind to two different tumor antigens – inhibit cancer growth by hitting multiple targets simultaneously. Now, three Johns Hopkins research groups describe promising early evidence that designing bispecifications so that it binds to tumor antigens at the same time, and T cells can provide a viable approach to creating immune-oncological drug treatments.
One Hopkins team has withdrawn on p53, a well-known tumor-suppressor gene that is inactivated in some cancers, but it is extremely difficult to reactivate with drugs.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 attaches to a fragment of the mutated p53 protein and another 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. This caused the tumors to shrink.
Even when the p53 target was present at an “extremely low” level on the surface of the tumor cells, the researchers write, the bispecific antibody could still activate T cells to fight cancer.
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A second study, published in Science Immunology, showed a bispecific antibody against another cancer-driving mutant gene, which was difficult to target: RAS. Mutant RAS proteins are troublesome targets for drugs because they are often expressed at low levels.
The researchers developed mutation-associated antibodies (neoantigen-directed antibodies) and then grafted them onto a bispecific antibody involving T cells. They tested the resulting bispecific antibody in human cell lines of patients with lung and pancreatic cancer, which showed that it can destroy tumor cells with low levels of mutated RAS, while leaving cells with normal RAS alone.
The study “shows that it is possible to generate bispecific antibodies that are very specific”, the authors wrote and “are able to achieve target death at very low antigen density.” In fact, they have become accustomed to bispecific antibodies targeting other cancer-driving proteins, they said.
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The third Hopkins team aimed to target cancerous T cells that drive certain leukemias and lymphomas – but to do so without harming normal T cells. Therefore, 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 research lines of patients and mouse models of leukemia and lymphoma, the bispecific antibodies targeted and killed the cancer-driving T cells without affecting healthy T cells, and the cancer relapsed, the researchers reported in Science Translational Medicine.
All three bispecific approaches can offer alternatives to personalized immunotherapies, such as designed CAR-T cells constructed from immune cells of individual patients. There is already one bispecific antibody on the market, Amgen’s Blincyto, which has been approved for the treatment of some patients with acute lymphoblastic leukemia (ALL) in B cell. And a few more are in clinical trials.
But bispecific antibodies present some challenges that need to be addressed before the three approaches proposed by Hopkins researchers can continue to treat cancer, said Jon Weidanz, Ph.D., of the University of Texas, in a accompanying editorial published. in science.
First, these drugs tend to be small molecules that are quickly removed from the bloodstream, making it necessary to administer them continuously, Weidanz wrote. By adding elements to bispecific antibodies to improve half-life, it will become larger, which can reduce their potency, he added.
The studies ‘provide a possible pathway to the achievement of on-the-shelf, protein-based immunotherapeutics for the treatment of cancer’ with specific antigens or mutations, Weidanz wrote. “However, more work will be needed to address the issues addressed by these three studies and others before this ambitious goal can be achieved.”