Research and Discovery Programs
T cell Engagers
We utilize the natural features of IgM antibodies to create unique and patent protected bispecific T cell engagers, which may have the potential to kill cancer cells through T cell directed cellular cytotoxicity (TDCC) and complement-dependent cytotoxicity (CDC) while maintaining a favorable tolerability and safety profile. Bispecific T cell engagers are designed to simultaneously target a desired tumor associated antigen on a cancer cell and CD3 (a protein that is expressed on the surface of T cells) and redirect the T cells to kill the cancer cells.
In contrast to other bispecific antibody formats that bind to one or two target molecules on the surface of the cancer cell and to one CD3 molecule on the surface of the T cell, our IgM bispecific format provides 10 binding units to the cancer cell and one binding unit to CD3. Our IgM bispecific antibodies may successfully bind to cancer cells for longer periods and with more avidity compared to IgG bispecific antibodies, which may prove to be particularly advantageous for those cancer cells that express relatively lower amounts of the targeted protein on their surface.
We have begun conducting research on a broad range of cancer cell targets with our proprietary bispecific T cell engaging IgM antibodies, in addition to our lead CD20 x CD3 T cell engager. We believe that our IgM platform will allow for treatment with a relatively favorable cytokine release profile with respect to a variety of cancer cell targets, including those targets that are expressed at a relatively low level on the surface of cancer cells.
CD123 x CD3
Phase 1 clinical studies have been conducted with CD123 x CD3 bispecific antibodies by other companies. Although early signs of clinical efficacy have been reported in some patients, severe CRS and some patient deaths have also been observed with these T cell engaging antibodies directed at CD123. We believe that the cytokine release profile of our IgM platform may allow us to effectively treat these patients with an acceptable tolerability profile.
CD38 x CD3
As with CD20, we believe that bispecific T cell engagers directed at CD38 may be able to effectively treat some relapsed or refractory MM patients. In vitro studies with CD38 expressing MM cell lines have demonstrated that CD38 x CD3 IgM antibodies can induce potent TDCC killing of MM cancer cell lines, and these IgM bispecific antibodies were shown to be more potent in vitro than an IgG antibody that uses the antibody-dependent cellular cytotoxicity (ADCC) mechanism of killing.
Other Cancer Cell Targets x CD3
The high avidity provided by the 10 binding units of our IgM platform may also provide significant advantages in the treatment of patients with solid tumors compared with IgG based bispecific formats. For example, our high avidity format may allow us to target cancer cells that express relatively low cell surface levels of the targeted tumor associated antigen. It may also allow us to target difficult solid tumor targets such as carbohydrates and glycosylated proteins that are challenging to bind with IgG antibodies.
Receptor Cross-linking Agonists
We are also developing IgM antibodies that bind to members of the tumor necrosis factor receptor superfamily (TNFrSF). Members of the TNFrSF must be bound in clusters of at least three in order to send a strong biological signal to the cell. This family includes targets that will cause the death of cancer cells, such as DR5, and targets that will cause the proliferation of T cells, such as OX40 and GITR.
There have been multiple attempts to create IgG based therapeutic antibodies directed at DR5, OX40 and GITR. However, since IgG antibodies naturally bind only two DR5, OX40 or GITR cell surface proteins, their bivalent nature inherently limits their signaling efficacy. In contrast, we are utilizing the 10 binding units of IgM antibodies to more efficiently cross-link these molecules on the cell surface.
In addition to DR5 program, we are conducting research on OX40 and GITR with the goal of enhancing the activity and proliferation of T cells in order to improve immune system responses to cancer.
We are leveraging our IgM platform to create bispecific IgM antibodies to deliver potent, immune stimulating cytokines that are targeted with the strong and durable binding power of the 10 binding units of an IgM antibody. These IgM antibodies will target the delivery of IL-15 with the goal of inducing immune cell stimulation and proliferation.
Targeted delivery of cytokines is designed to reduce systemic toxicities of cytokine therapy while enhancing immune system activity in the area of the target. Stimulation of the IL-15 pathway may be important in strengthening and maintaining both endogenous and synthetic T cell immune responses.