Bispecific antibodies treat cancer in mouse models

L.Using a patient’s own immune system to fight cancer has long been a goal of researchers and doctors. For example, in T cell therapy with chimeric antigen receptors (CAR), doctors extract a patient’s T cells and then introduce genetic material that trains those cells to recognize tumor antigens that they normally overlook. When reintroduced into the body, the goal is for the CAR T cells to locate and kill the cancer cells. While strategy can make a difference – one study put 22 of 27 patients with severe B-cell lymphoma into complete or partial remission – making CAR-T cells is time-consuming and sometimes causes nasty side effects, similar to traditional cancer treatments that indiscriminately damage non-cancerous cells.

Another immunotherapy strategy using antibodies against cancer-specific peptides can effectively target tumor cells for destruction, but these targets are often within cells and inaccessible at the cell surface.

In three studies published on March 1, the researchers developed so-called bispecific antibodies to firmly bind even very small amounts of cancer-related peptides with one of their arms and to recruit a T cell with the other to destroy the peptide-presenting cell. In mice, these antibodies specifically kill cancer cells, both solid tumors and T-cell leukemia, while most healthy cells are preserved, the studies showed.

“The unifying principle is to adapt immunotherapies more precisely on the one hand, and to pursue goals that are traditionally considered non-targeted on the other,” says Jonathan Schatz, oncologist and researcher at the University of Miami was not involved in the work. “It boils down to new ways of personalizing immunotherapy.”

Bispecific antibodies target rare antigens

These two goals were behind the work of a group led by oncologist Bert Vogelstein and cancer biologist Kenneth Kinzler of the Ludwig Center at Johns Hopkins Medicine. The gene encoding tumor suppressor p53 is one of the most commonly mutated in cancer, but there is no good therapeutic to target the mutated protein. Cancer cells present fragments of this protein complexed with the major histocompatibility complex (MHC), human leukocyte antigen (HLA), but there are typically only a handful of these HLA-p53 complexes on the cell surface.

For your studies in science, The researchers generated an antibody arm that was highly specific for the HLA-p53 combination – so specific that it could distinguish a mutant p53, which differed from the wild-type p53 by one amino acid. This specificity meant that this arm found the small number of these complexes on the surface of a tumor cell and was also tightly bound and did not fall off. They linked this antibody fragment to another arm that binds CD3, a T cell surface receptor and activator.

The resulting bispecific antibody recruited T cells to destroy cancer cells with the mutated p53 protein on their surface in both cell culture and mice. The researchers injected immunodeficient mice with both human T cells and mutated p53 tumor cells. Once the tumors were identified, the team infused the mice with bispecific antibodies. The tumors stopped growing and regressed in mice that received the therapeutic but not in controls that received an antibody that was supposed not to bind the target. in the Scientific immunology, They showed similar effectiveness for a bispecific antibody targeting proteins from mutants RAS Oncogenes in cell culture and in mice.

“This particular technology, these bispecific antibodies per se, is not new. A normal antibody can use one arm to grab a tumor antigen that is highly expressed [levels] She can grab the T cell on the tumor cell and with the other arm, ”says Theresa Whiteside, who studies immunotherapy at the University of Pittsburgh and was not involved in the work. The US Food and Drug Administration approved the first bispecific antibodies against CD19 and CD3 against acute lymphoblastic B-cell leukemia in 2015 and has since approved at least five more. Many more are in the clinical trial stage. However, the use of these “high affinity antibody fragments provides a very sensitive means of detecting a peptide presented in minute amounts by MHC,” she adds.

Bispecific antibodies instead of CAR T cells

The most successful use of CAR T cells has been in the treatment of B cell-related blood cancers. However, the victims of treatment are healthy B cells. Killing T cells has far worse effects on the immune system than breaking down B cells. Therefore, immunotherapy has not been used successfully in the treatment of T cell-derived cancers. “The problem … If you design a T-cell to attack a T-cell antigen, there is this phenomenon called fratricide, in which the engineered T-cells kill each other before they ever do anything to the tumor “Says sweetheart.

In their study in Scientific translational medicine, Hopkins employees tested whether bispecific antibodies would avoid killing healthy T cells. One way of classifying T cells is to determine which of 30 types of so-called T cell receptor β chains they present on their cell surface. A cancer will consist of clones with the same β chain, so the researchers made a bispecific antibody with the CD3 effector binding fragment on one side and an arm directed to the relevant β chain antigen on the other . In culture and in mice, the bispecific antibody created a bridge between the two T cells and facilitated the destruction of malignant cells and healthy cells with the same antigen of the β chain, but left the other healthy T cells intact.

In theory, this approach should be able to remove all leukemic T cells, says Brian Lichty, who studied anti-tumor immune responses at McMaster University in Canada and did not participate in the work. There are some unanswered questions about either application of the approach, including how widespread the development of antibodies to certain HLA-mutated peptide combinations will be, and whether or not eradicating this fraction of T cells will have immunological consequences. “At least until your immune system has recovered, you might be temporarily susceptible to certain infections, but there’s no way you can know until you test this clinically.”

“It will be a few more years before all of these preclinical developments are translated into clinical studies. . . because we have to optimize the bispecific antibodies to ensure that they are safe for humans, ”explains Shibin Zhou, cancer biologist at the Ludwig Center and co-author of the studies The scientist. To facilitate the commercialization of these and other cancer-related technologies, the researchers founded several companies, serve on their boards and advise them, including Exact Sciences, Thrive Early Detection and Personal Genome Diagnostics.

J. Douglass et al., “Bispecific Antibodies Against Mutants RAS Neoantigens ” Scientific immunology, doi: 10.1126 / sciimmunol.abd5515, 2021.

EH-C. Hsiue et al., “Targeting a Neoantigen Derived from a Common TP53 Mutation,” science, doi: 10.1126 / science.abc8697, 2021.

S. Paul et al., “TCR Beta Chain Targeted Bispecific Antibodies for the Treatment of T-Cell Cancer”. Scientific translational medicine, doi: 10.1126 / scitranslmed.abd3595, 2021.

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