Bispecific antibodies, drugs designed to 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 bispecifics to bind simultaneously to tumor antigens and T cells could offer a viable approach to creating immunological-oncological drug treatments for sale.
A Hopkins team zeroed in on p53, a well-known tumor suppressor gene that is inactivated in some cancers, but has been shown to be exceptionally difficult to reactivate with medication. Hopkins researchers designed a bispecific antibody that could target the mutant p53 protein without interfering with intact p53 in normal cells, they told the journal Science.
The bispecific antibody they designed has one arm that binds to a fragment of the mutated p53 protein and another that binds to a T cell. In multiple myeloma mouse models, the bispecific antibody went stimulate T cells to kill p53 mutant cancer cells, the researchers reported. This led to the reduction of tumors.
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. .
RELATED: Triggering the TP53 Cancer Gene in Leukemia with a New Combination Treatment
A second study, published in Science Immunology, turned a bispecific antibody against another mutant gene that drives cancer and has been difficult to target: RAS. Mutant RAS proteins are complicated pharmacological targets because they are often expressed at low levels.
The researchers developed antibodies targeted by mutation-associated neoantigens (MANA bodies) and then grafted them into a bispecific antibody involving T cells. They tested the resulting bispecific antibody in human cell lines of cancer patients. of lung and pancreas, demonstrating that it could destroy tumor cells with low levels of mutated RAS, while leaving alone cells with normal RAS.
The study “demonstrates that it is possible to generate highly specific bispecific antibodies,” the authors wrote, and “capable of inducing target cell death at very low antigen densities.” In fact, they have become accustomed to creating bispecific antibodies to other proteins that drive cancer, they said.
RELATED: The revolution makes a $ 238 million IPO to push the KRAS pipe into the clinic
Hopkins ’third team set out to target cancer T cells that lead to certain leukemias and lymphomas, but do so without harming normal T cells. Therefore, they designed bispecific antibodies to target either of two specific regions that were likely to be present in malignant T cells, TRBV5-5 or TRBV12.
In cell lines of leukemia and lymphoma models of patients and mice, bispecific antibodies targeted and killed the cancer-causing T cells without affecting healthy T cells and the cancer receded, the researchers in Science Translational Medicine.
All three bispecific approaches could offer alternatives to personalized immunotherapies, such as designed CAR-T cells that are constructed from each patient’s immune cells. A bispecific antibody is already on the market, Amgen’s Blincyto, approved to treat some patients with acute B-cell precursor lymphoblastic leukemia (ALL). And there are several more 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, Jon Weidanz, a doctoral student at the University of Texas, said in an attached editorial published in Science.
On the one hand, these drugs are usually small molecules that are rapidly removed from the bloodstream, making continuous infusion necessary, Weidanz wrote. Adding elements to bispecific antibodies to improve half-life would make them bulkier, which could decrease their potency, he added.
The studies “offer a potential way to get tailor-made, protein-based immunotherapies 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.”