Nature: Sanofi develops three specific antibodies to improve the antitumor effect of T cells

Single specific monoclonal antibodies that can only specifically bind to one target are the first widely used cancer immunotherapies (such as anti-PD-1 / PD-L1 antibodies) Then, bispecific antibodies appear in people's vision as cancer immunotherapy One end of these antibodies can bind to the antigen on the surface of cancer cells, and the other end can bind to the T cell receptor on the surface of T cells to recruit and activate T cells to kill cancer cells (for example, bluemomab of amjin company) In a recent study published in nature cancer, Sanofi's R & D team developed a three-specific antibody, which can not only bind to cancer-related antigens and receptors that activate T cells, but also to another target on the surface of T cells, so as to extend the anti-cancer activity of T cells At the same time, in the journal Nature, Dr Alfred garfall and Dr Carl June of the University of Pennsylvania commented on this study, pointing out that the use of three specific antibodies to treat cancer is an important conceptual progress Dr Alfred garfall and Dr Carl June commented on the study in the journal Nature (photo source: reference [1]) Bispecific antibodies, such as bluemomab, have been successfully used in clinical trials Blinatumomab is a bispecific antibody targeting CD19 antigen on the surface of cancer cells and CD3 receptor on the surface of T cells It can double the remission rate and survival period of patients in the treatment of B-ALL The efficacy of these bispecific antibodies is based on the effective activation of T-cell antitumor activity However, when T cells are activated, not only the CD3 receptor-mediated signal pathway is activated, but also a costimulatory receptor-mediated signal pathway called CD28 is activated This dual activation can ensure that T cells are not only activated, but also can maintain long-term activity To activate both CD28 and CD3 receptors, Sanofi's researchers designed a Trispecific antibody that binds to CD38 antigens on the surface of multiple myeloma (mm) cells and CD3 and CD28 antigens on the surface of T cells Activation of CD28 receptor can stimulate the expression of bcl XL protein BCL XL can help to block the apoptosis of T cells, thus prolonging the activity of T cells CD28 as a costimulatory receptor has been used in car-t therapy Some receptors expressed by car-t cells contain costimulatory domains of CD3 and CD28 Moreover, CD28 is often expressed on the surface of MM cells, so this design may also improve the affinity of three specific antibodies to MM cells Action mechanism of Trispecific antibody (picture source: reference [1]) In vitro, compared with the approved monoclonal antibody daratumumab, the proportion of cancer cells cleaved by the three specific antibodies was increased by 3-4 times Moreover, in the mouse model of multiple myeloma, the three specific antibodies can also reduce the size of transplanted tumor in a dose-dependent manner ▲ the three specific antibodies significantly increased the proportion of cancer cell lysis (above) and reduced the tumor volume in a dose-dependent manner in the mouse model (photo source: reference [2]) Researchers still need to test the safety of this innovative antibody The common side effect of cancer immunotherapy that stimulates T cell activity is cytokine release syndrome, which is caused by over activation of T cells In the non-human primate model, this three-specific therapy shows controllable safety, but its safety needs to be verified in the human body and MM patients According to a review published in nature, patients with multiple myeloma always need new treatments, because even effective treatments like car-t can only bring temporary relief to most patients The three specific antibodies may provide a flexible platform to deliver precise immune regulation signal combination according to the tumor microenvironment, which is more safe and effective than the combination therapy composed of three single specific antibodies reference material: [1] Garfall and June (2019) Trispecific antibodies offer a third way forward for anticancer immunotherapy Nature, doi: 10.1038/d41586-019-03495-3 [2] Wu et al., (2019) Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation Nature Cancer, https://doi.org/10.1038/s43018-019-0004-z A kind of