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 immunotherapies that enable the patient’s immune system to identify and kill cancer cells. Today there are many types of antibody-based immunotherapies, including monoclonal antibodies, CAR-T cells and bispecifics.
Antibody-based immunotherapies are designed to specifically recognise particular targets on a cancer cell. These targets are known as "antigens". When an antibody (the key) detects its antigen (the lock) on a cancer cell, the antibody will attach to the antigen on the cancer cell, triggering 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 the antigen on the cancer cells and to destroy those cells.
To add another layer of complexity, cells don’t express only one antigen but many, and many cell types – even those that are healthy normal cells - can express the same antigen. The cancer cells that cause multiple myeloma express many of the same antigens as healthy bone marrow and blood cells.
Our immunotherapies specifically target cancer cells, making them different to those on the market.
HaemaLogiX has discovered two antigens that are found on the cell surface of cancer cells in patients with myeloma and AL amyloidosis, on some lymphoma and Waldenstrom’s macroglobulinemia cells. These antigens are also found on occasional mononuclear cells in tonsils and in secondary mucosal lymphoid tissue and in vitro derived plasmablasts but – most importantly - not on any other normal immune cells or tissues.
These two unique antigens are called kappa myeloma antigen (KMA) or lambda myeloma antigen (LMA).
The goal of our antibody therapy is to target KMA or LMA. We have a key focus on treating multiple myeloma, and we are investigating the application of our immunotherapies as a treatment for AL Amyloidosis.
Multiple myeloma is known as a ‘monoclonal’ cancer, meaning that all the myeloma cells in one person will have come from one original cancer 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.
Treatments that target antigens found only on cancer cells have a better safety profile than those that target antigens found on both normal and cancer cells.
As KMA and LMA are specific to the cancer cells in multiple myeloma patients, targeting them with our unique antibodies should only kill the myeloma cells, while not attacking other normal 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. The majority of cancer patients are treated with various combinations of drugs that act in different but in complementary ways. This means that patients who relapse or don’t respond to certain drug combinations can subsequently be treated with different combinations.
Studies have shown that the immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide, which are standard of care for treatment of multiple myeloma, increase the number of KMA targets on myeloma cells and enhance the ability of KappaMab to kill the cancer cells.
Preclinical work with the lambda antibodies (LambdaMabs) has also shown that they only bind to LMA that is found on cancer cells in patients with myeloma and AL amyloidosis. LMA is also found on occasional mononuclear cells in tonsils and in secondary mucosal lymphoid tissue, it is not found on other normal immune cells.
KappaMab and LambdMab
Monoclonal antibodies (mAbs) have two antigen binding regions and one constant region that other immune cells, such as natural killer (NK) cells, can attach to and kill the cancer cell that the antibody is bound to. When our mAbs are infused into a person, the two antigen binding regions attach to specific antigens on the target cells (the cancer cells) in the body. Once this binding occurs, a natural killer (NK) cell from the immune system binds to the constant region of the antibody. This binding activates the NK cell, which results in killing of the cancer cell.
It is important to note that, as stated previously, HaemaLogiX's monoclonal antibodies do not bind to other normal immune cells, thus leaving them unharmed and able to function normally.
To kill myeloma cells, we’re developing our proprietary monoclonal antibodies KappaMab (for kappa-type multiple myeloma) and LambdaMab (for lambda-type multiple myeloma).
Several drugs that are currently in use to help treat multiple myeloma can be used in combination with KappaMab and LambdaMab to help make them more effective at killing the cancer cells. Giving a patient an immunomodulatory drug (IMiD), such as lenalidomide or pomalidomide will make the cancer 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 cancer 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 cancer cell and recruiting the NK cells to kill the cancer cells. This increase in antigen number following pre-treatment with an IMiD is a mechanism that should increase the efficacy of our antibodies in the treatment of myeloma.
CAR T cell Therapies
KMA.CAR T and LMA.CAR T
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 genetically modified. During this process, specific genetic code created to form the binding domain of KappaMab and the intracellular activation domains of a T cell is introduced into the T cells using a viral vector. This genetic code creates a chimeric antigen receptor (CAR) in the T cells so that they express the KMA binding region on their cell surface; this expressed binding region on the T cell surface will specifically target KMA on the cancer cells.
These KMA.CAR T cells are then cultured to increase in numbers to produce billions of KMA.CAR T cells and infused into the same patient they came from, where they target and kill the cancer cells. In general CAR T cells are now being used in earlier stages of cancer treatment.
Kappa bispecific antibody and Lambda bispecific antibody
A bispecific antibody is designed to bind both an antigen on a cancer cell and an antigen on a normal T cell so that they are linked to one another. Connecting the two cells activates and enables the T cell to directly kill the cancer cell. There are a number of different bispecific constructs and recently they have been composed of whole antibodies that can survive for several weeks in the patient’s body. One of these constructs is shown above and in this construct one of the target binding sites of the bispecific antibody binds to the antigen on the cancer cell, and the other arm binds to a T cell. This binding brings the two cells together and initiates a T cell immune response that is very effective at killing the cancer cells.