How are Bispecific Antibodies Used?
- Bispecific antibodies are a new type of immunotherapy, which uses the body’s own immune system to fight cancer.
- They simultaneously bind to tumor cells and the immune system cells, prompting the latter to kill the former.
- While only a few bispecific antibodies have been approved by the FDA, many more are currently in development.
What are Antibodies?Antibodies that exist in nature are unique, Y-shaped protein molecules. The two arms at the top of the Y shape usually bind to two identical molecules, the so-called antigen, which is normally present on disease-causing agents, such as bacteria and fungi. This binding usually springs the immune system into action, which ultimately results in the elimination of the offending agent. Although all antibodies are composed of similar Y-shaped units, how many of these units are present and how they are arranged differs between the different forms of antibodies. There are five different forms, namely, IgA, IgD, IgE, IgG, and IgM. IgG antibodies have just one Y-shaped unit. IgM, on the other hand, has five units joined together like a pentagram.
How are Bispecific Antibodies Different?
Bispecific antibodies, on the other hand, are not found in nature. They are engineered in the laboratory using various modern technologies. In contrast to natural antibodies, they have at least two arms that can bind to two different antigens or two different sites on the same antigen.
Most bispecifics are engineered to look like single-unit, Y-shaped IgG antibodies. Dr. Catherine Diefenbach, Director of the Clinical Lymphoma program at Perlmutter Cancer Center, expresses, "most of the [bispecifics] are IgG-based. There is one pentavalent IgM-based antibody." A pentavalent antibody is one which has five Y-shaped units, as described above.
Why Do We Need Bispecific Antibodies?
The human immune system is composed of many categories of cells, each engineered by nature to protect the body against infections from bacteria, viruses, and fungi. These cells include macrophages, dendritic cells, natural killer cells, B-cells, and T-cells. Each category has unique functions. B-cells, for example, are antibody factories, generating them in response to a host of pathogens that find their way into the body.
T-cells are the body's main defense mechanism against cancer. Yet these cells can frequently become dysfunctional inside tumors. Or more commonly, they can be fooled by the cancer cells into thinking that cancer cells are just normal body cells that should be spared from destruction. There are many ways in which cancer cells commit this deceit. They may start to express some of the same proteins as normal body cells, which blind the T-cells to the true nature of the cancer cells.
For example, some tumor cells may start to express a protein called PD-L1. This protein can couple with PD-1 proteins, which are expressed on the surface of many immune cells. This protein coupling renders the tumor cells essentially invisible to and safe from the immune system.
These T-cells need not be a lost cause. Certain immunotherapies can throw a wrench in the immune system evading tactics of cancer cells, either by blocking tumor proteins that turn immune cells off or by activating T-cells anyway, regardless of the inhibitory signals from the tumors. Bispecific antibodies, on the other hand, can bind one protein on the tumor cells and a different protein on immune cells, thereby prodding the latter to eliminate the former.
How Do Bispecific Antibodies Work?
"A bispecific antibody is an antibody that has at least two arms, usually one to [bind] to a T-cell, and one to [bind] to a tumor target," says Dr, Diefenbach. The arm that binds the T-cells usually targets common proteins present on its surface, such as CD3.
When both arms engage their respective targets, the T-cells are brought into close proximity with the tumor cells. This activates the T-cells, impelling them into action against the tumor cells. In somewhat of a domino effect, several kinds of T-cells are activated en masse. All in all, the bispecific antibodies can help T-cells mount a vicious attack on the tumor cells that can ultimately result in cancer elimination.
Bispecific antibodies have been most successfully used in blood cancers, such as follicular lymphomas, which are a type of cancer originating from white blood cells. In fact, the bispecific mosunetuzumab was recently approved by the FDA for follicular lymphoma cases that fail or are resistant to traditional treatments.
What are the Side Effects?
Per Dr. Diefenbach, "as a class, bispecific antibodies tend to have some of the same side effects as CAR T-cell therapy but at a much lower level." She continues, "[they] all generally tend to occur in the first cycle of therapy, sometimes the beginning of the second cycle. Subsequently, there is very low toxicity with these therapies." The main side effects of bispecifics include:
Cytokine Release Syndrome (CRS)
This signifies a large-scale release of cytokines into the bloodstream by activated immune cells. Cytokines are small molecules that have a variety of functions within the immune system, such as marking the area of the body where immune cells are most needed. The unchecked cytokine release that occurs during CRS, however, can cause a host of undesirable effects, such as fever, headaches, abnormally low blood pressure, difficulty breathing, and heartbeat abnormalities. The severity of these side effects can vary from person to person, and from mild to severe and deadly.
Bispecific antibodies can cause T-cells to stick to the insides of blood vessels and eventually leak into organs, including the central nervous system (CNS; brain and the spinal cord). There, T-cells can produce cytokines that lead to inflammation. This, in turn, can attract other types of immune cells into the CNS, which can worsen the inflammation and cause toxicity to the neurons. This phenomenon is termed neurotoxicity.