The ability to control the immune system through immunotherapy, such as checkpoint inhibitors and genetic modification of T lymphocytes, has shown great promise in the fight against cancer, however, many malignancies remain unresponsive to these therapies. Bispecific antibodies, which simultaneously target cancer antigens and engage the T cells to activate the immune system to specifically target tumors has shown some clinical efficacy. Now, in a landmark study published in Nature Cancer, find out how adding a third functionality to the bispecific antibody can significantly enhance T cell activation through co-stimulation and tumor targeting to reduce overall tumor burden.
This trispecific antibody was engineered to bind three different targets: 1) the cancer antigen CD38, which is an antigen highly expressed by malignant myeloma cells and the current target of monoclonal immunotherapy 2) CD3, which is a T cell receptor activation signal that leads to cytokine secretion, and 3) CD28, which is a survival signal inhibiting programmed cell death. The multi-functionality of this trispecific antibody allows the targeting of the tumor while providing co-stimulatory signals that promote T cell expansion and survival in order to increase elimination of the tumor. To create this antibody, researchers used the trispecific antibody platform that has been previously reported to create an antibody that bound three different sites on the HIV viral envelope.
Using the cross-over dual variable (CODV) bispecific antibody format, Wu et al. evaluated combinations of CD3 and CD28 variable fragments for sustained activation of T cells. Mutation of the binding sites revealed that each component was necessary for optimal T cell activation. In vitro testing of the optimal CD38/CD3xCD28 trispecific antibody preferentially stimulated proliferation of both CD4+ T helper 1 cells and memory and effector CD8+ T cells, possibly contributing to improved immunity against non-CD38 expressing tumor cells. Additionally, engagement of CD28 promoted T cell proliferation and expression of pro-survival protein Bcl-xL as expected. Interestingly, the engineered trispecific antibody showed a 3- to 4-log higher cytolytic activity in vitro against CD38high and CD38low compared to the clinically approved CD38-targeting monoclonal antibody daratumumab. In order to test the effects of the multi-functional trispecific antibody on tumor regression, a humanized mouse model of multiple myeloma was used. In vivo administration of this trispecific antibody exhibited a dose-dependent reduction in tumor burden even at low doses. Some cancer immunotherapies have been associated with cytokine-related toxicities in human. To assess the safety of the antibody, non-human primates were used. Administration of the trispecific antibody in non-human primates revealed potent stimulation of memory and effector T cell proliferation and targeting with low toxicity at tolerable doses.
This study shows the potential for novel multi-functional antibodies that can deliver two signals to T cells while simultaneously directing them to cancer cells, resulting in enhanced T cell activation and tumor targeting. These antibodies have opened the door to the ability to engineer antibodies that can target any cancer antigen or combination of antigens while precisely controlling the stimulation and activation of the immune system. The next step will be to evaluate antibody safety and efficacy against cancer in humans. Although anti-therapeutic response could still occur in clinical trials, current bispecific antibodies using a related format have been well tolerated in humans. This multi-specific targeted approach increases the immunotherapeutic options available and increases the ability to harness the power of the body’s immune system to defeat cancer.