igm-CD20-hero-11

IGM-2323: CD20 x CD3 Bispecific IgM Antibody

Our lead product candidate is IGM-2323, a CD20 x CD3 bispecific IgM antibody designed to treat patients with B cell Non-Hodgkin’s lymphoma (NHL) and other B cell malignancies. Our initial therapeutic goal with IGM-2323 is to safely and effectively treat relapsed/refractory B cell NHL patients. CD20 is a protein that is commonly expressed on the surface of malignant B cells, while CD3 is a protein that is expressed on the surface of T cells and is an essential activating molecule of the T cell.

CD20xCD3 IgM:  T cell to cancer cell engagement
for hematologic and solid malignancies

In contrast to other bispecific antibody formats that bind to one or two CD20 molecules on the surface of the cancer cell and to one CD3 molecule on the surface of the T cell, IGM-2323 has 10 binding units to CD20 and one binding unit to CD3. We believe that IGM-2323 with its 10 binding units for CD20 may successfully bind to CD20 expressing cancer cells with more avidity compared to an IgG bispecific antibody with only one binding unit for CD20.  We believe the extra binding units of IGM-2323 may prove to be particularly advantageous for those cancer cells that express relatively lower amounts of CD20 on the cancer cell surface. This may include those clinical circumstances in which CD20 expression has been reduced due to prior treatment with other anti-CD20 antibodies, such as rituximab.

IGM-2323 has also been shown to have a lower cytokine release profile associated with the TDCC mechanism of action compared to an IgG based CD20 x CD3 antibody with the same CD20 and CD3 binding units, when tested in vitro with human T cells and human B cells.

IGM-2323 is designed to simultaneously and stably bind a CD20 expressing cancer cell as well as CD3 on a cytotoxic T cell, bringing both cells into close proximity. This interaction mimics the normal T cell activation pathway leading the T cell to recognize and kill the cancer cell by releasing cytotoxic biochemicals (perforins and granzymes) that penetrate and perforate the cancer cell.

This T cell directed cellular cytotoxicity (TDCC) mediated killing mechanism of IGM-2323 on CD20 expressing cancer cells is shown in the diagram below.

IGM-2323 Binding to a CD20 Positive Cancer Cell and Inducing TDCC

 

Schematic diagram of IGM-2323 binding a CD20 expressing B cancer cell and a CD3 expressing T cell for TDCC. Shown is the IGM-2323 induced T cell release (degranulation) of cytotoxic biochemicals from T cell lytic granules in close proximity to the cancer cell to induce perforin pore formation in the cell membrane, allowing cell entry of the cytotoxic biochemicals and induction of cancer cell death.

 

IGM-2323 also employs an additional mechanism to kill CD20 expressing cancer cells, known as complement dependent cytotoxicity (CDC). CDC is a mechanism by which antibodies can mediate specific targeted cell killing by activating the complement system. Components of the complement system are naturally present in humans, and IgM antibodies are the most efficient antibodies at engaging the complement system for CDC, with an approximately 100 fold increase in CDC relative to comparable IgG CD20 antibodies. The CDC mediated killing mechanism of CD20 expressing cancer cells by IGM-2323 is shown in the diagram below.

IGM-2323 Binding to a CD20 Positive Cancer Cell and Inducing CDC

 

Schematic diagram of IGM-2323 binding a CD20 expressing B cancer cell and recruiting components of the complement system from the serum to induce complement dependent cytotoxicity (CDC) through formation of a membrane attack complex.