One of the key challenges with fighting cancer is that cancer cells are able to evade the immune system. In order to kill cancer cells, researchers have developed monoclonal antibodies that specifically recognise one particular target, called an antigen, on a cancer cell. When an antibody (the key) sees a cancer cell with the right antigen (the lock), the antibody will attach to the antigen on the cancer cell, and this will trigger a series of immune system-related events that will destroy the cancer cell. In essence, modern antibody therapies ‘prime’ or teach our immune system to recognise that the antigen on the cancer cells is foreign and to destroy those cells.
To add another layer of complexity, cells don’t express only one antigen but many, and many cell types can express the same antigen. The malignant plasma cells – the B cells that cause multiple myeloma – express many of the same antigens as healthy bone marrow and blood cells, however HaemaLogiX has discovered two antigens that are only found on the cell surface of the malignant myeloma cells, on some lymphoma and Waldenstrom’s macroglobulinemia cells, occasional tonsillar B cells but not on any other normal immune cells or human tissue.
These two unique antigens are called kappa myeloma antigen (KMA) or lambda myeloma antigen (LMA). Multiple myeloma is known as a monoclonal cancer, meaning that all the cancerous myeloma cells in one person will have come from one malignant cell. Hence, a patient will either express KMA or LMA on their myeloma cells. In general two thirds (~70%) of myeloma patients cells express KMA and one third (~30%) express LMA.
The goal of our antibody therapy is to target KMA with our proprietary monoclonal antibody KappaMab, and LMA with our monoclonal antibody LambdaMab to kill myeloma cells.
As these antigens are specific to the malignant cells in multiple myeloma patients, targeting them with our unique antibodies should kill the myeloma cells, while not attacking healthy immune cells. This offers a unique advantage compared to other antibodies on the market or in clinical trials.
One extremely common feature of cancer treatment is the use of combination therapy. In most cancers the vast majority of patients are treated over time with combinations of drugs that act differently but in complementary ways. Studies have shown that the immunomodulatory imide drugs (IMiDs) such as lenalidomide and pomalidomide, which are clinically approved drugs that are commonly used to treat myeloma, increase the number of KMA targets on myeloma cells and enhance the ability of KappaMab to kill the malignant cells.
Monoclonal antibodies (mAbs) have several binding regions. When our mAbs are infused into a person, two of the regions bind to specific antigens on target cells in the body (the cancerous cell, or myeloma plasma cell). Once this binding occurs, a natural killer (NK) cell from the immune system binds to the third region of the antibody. This binding activates the NK cell, which results in killing of the cancerous cell.
It is important to note that, as demonstrated above, HaemaLogiX's monoclonal antibodies do not bind to healthy plasma cells, thus leaving them unharmed and able to function normally.
Several drugs that are currently in use to help treat Multiple Myeloma can be used with our antibodies to help make them more effective at killing the cancerous cells. Giving a patient an immunomodulatory imide drug (otherwise known as an IMiD), such as lenalidomide or pomalidomide will make the cancerous plasma cell express more of our target antigen (either KMA or LMA) on its cell surface. Hence, when our antibodies are infused into the patient, the cancerous plasma cell now has a much greater number of target antigens for our antibodies to bind to. This makes our antibodies much more effective at attaching to the cancerous cell and recruiting the NK cells to kill the cancerous cells. This increase in antigen number following pre-treatment with an IMiD is a mechanism that is unique to our KMA and LMA antigens in multiple myeloma.
CAR T cell Therapies
With CAR T cell therapy, a patient's own white blood cells are collected during a process called apheresis. Once apheresis is complete, the white blood cells are then cultured in a manufacturing facility, where they are modified. During this process, specific genetic code is introduced into the T cells using a viral vector. This genetic code causes the T cells to express our antibody on their cell surface; this expressed antibody on the T cell surface will specifically target the antigen on the cancerous plasma cells. These CAR T cells are then cultured to increase in numbers to billions of CAR T cells and infused into the same patient they came from, where they target and kill the cancerous plasma cells. CAR T cells are frequently used in a patient for whom all other treatments or standards-of-care no longer work.
A bispecific antibody is designed to bind an antigen at one end, and a T cell at the other end. As shown above, the top two arms of the antibody bind to the antigen on the cancerous cell, and the bottom arm binds to a T cell. This binding initiates an immune response that is very effective at killing those cancerous cells.