Sanofi's Trispecific Antibody Enhances T Cell-Mediated Antitumor Efficacy, Reports Nature Cancer

Monospecific monoclonal antibodies, which bind specifically to a single target, were the first cancer immunotherapies to achieve widespread use (e.g., anti-PD-1/PD-L1 antibodies). Subsequently, bispecific antibodies emerged as cancer immunotherapies; these antibodies bind to antigens on the surface of cancer cells at one end and to T-cell receptors on the surface of T cells at the other, thereby recruiting and activating T cells to kill cancer cells (e.g., Amgen’s blinatumomab). Recently, in a study published in Nature Cancer, a research team at Sanofi developed a trispecific antibody that not only binds to cancer-associated antigens and receptors that activate T cells, but also engages an additional target on the surface of T cells, thereby prolonging their anticancer activity. In a commentary published in Nature, Dr. Alfred Garfall and Dr. Carl June from the University of Pennsylvania highlighted this work, noting that the use of trispecific antibodies for cancer treatment represents a significant conceptual advance.

▲Dr. Alfred Garfall and Dr. Carl June commented on this study in Nature (Image source: Reference [1])

Bispecific antibodies, exemplified by blinatumomab, have achieved success in clinical trials. Blinatumomab is a bispecific antibody that simultaneously targets the CD19 antigen on the surface of cancer cells and the CD3 receptor on the surface of T cells. In the treatment of patients with advanced B-cell acute lymphoblastic leukemia (B-ALL), it has been shown to double both the remission rate and survival duration. The efficacy of this class of bispecific antibodies is based on the effective activation of the anti-tumor activity of T cells. However, when T cells are typically activated, not only is the CD3 receptor-mediated signaling pathway activated, but so is the signaling pathway mediated by CD28, a co-stimulatory receptor. This dual activation ensures that T cells are not only activated but also maintain sustained activity.

To simultaneously activate CD28 and CD3 receptors, researchers at Sanofi designed a trispecific antibody capable of binding to the CD38 antigen on the surface of multiple myeloma (MM) cells, as well as the CD3 and CD28 antigens on the surface of T cells. Activation of the CD28 receptor stimulates the expression of the Bcl-xL protein, which helps block T-cell apoptosis, thereby prolonging T-cell activity. As a co-stimulatory receptor, CD28 has already been utilized in CAR-T therapy; certain CAR-T cells express receptors containing the co-stimulatory domains of both CD3 and CD28. Furthermore, since CD28 is frequently expressed on the surface of MM cells, this design may also enhance the affinity of the trispecific antibody for MM cells.

▲ Mechanism of Action of Trispecific Antibodies (Image source: Reference [1])

In in vitro assays, the trispecific antibody increased the proportion of lysed cancer cells by 3- to 4-fold compared with the already approved CD38 monoclonal antibody daratumumab. Furthermore, in mouse models of multiple myeloma, this trispecific antibody also reduced the size of tumors xenografted into mice in a dose-dependent manner.

▲ Trispecific antibodies significantly increase the proportion of cancer cell lysis (upper panel) and reduce tumor volume in a dose-dependent manner in mouse models (Image source: Reference [2])

Researchers still need to evaluate the safety of this innovative antibody. A common side effect of cancer immunotherapies that stimulate T-cell activity is cytokine release syndrome, which results from excessive T-cell activation. In non-human primate models, this trispecific therapy demonstrated manageable safety; however, its safety profile must be validated in humans and in patients with multiple myeloma (MM).

A commentary published in Nature stated that patients with multiple myeloma have long been in need of new therapeutic options, as even highly effective treatments such as CAR-T cell therapy can only provide temporary remission for most patients. Trispecific antibodies may offer a flexible platform to deliver precise combinations of immunomodulatory signals tailored to the tumor microenvironment, thereby achieving greater safety and efficacy compared with combination therapies consisting of three monospecific antibodies.

References:

[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

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