Monoclonal antibodies as drugs

Antibodies constitute an important component of the immune system of mammals, including humans and mice. They are produced by B-lymphocytes and due to sophisticated genetic mechanisms every individual can make a vast variety of antibodies that can recognize and neutralize all kinds of harmful substances, such as viruses, bacteria and toxins.

By injecting human proteins into mice, such as the ‘on’ and ‘off’ receptors that regulate the activity of human immune cells, antibodies can be generated against these human proteins. This works, because there are differences between the human and mouse proteins, so the mouse immune system sees the human proteins as foreign, harmful substances that need to be eliminated. The B-lymphocytes making such antibodies can be isolated from these mice, and single cells producing one specific (monoclonal) antibody can be selected and subsequently grown to very large numbers. Such cultures of B-cells produce lots of this monoclonal antibody, enough to fill thousands of vials with this antibody, for use in pre-clinical experiments or as therapeutic drug in patients.

In this manner, monoclonal antibodies have been made against the aforementioned ‘on’ and ‘off’ receptors on immune cells. The antibodies against the ‘off’ receptors can be used to block the action of these receptors, and thereby neutralize suppressive signals that prevent immune cells from becoming activated against, for instance, tumors. The antibodies against ‘on’ receptors act as artificial stimulatory signals and thereby ‘wake up’ immune cells that were inactive due to lack of stimulatory signals and/or the presence of suppressive signals.

The IACT project focuses on the latter class of stimulatory antibodies: agonist immunostimulatory antibodies (agonist IS-Abs). The antibodies studied and produced in the context of this project react against one of three selected ‘on’ receptors on immune cells, with the following names: CD40, OX40 and CD137/4-1BB. Each of these receptors is expressed on a different type of immune cell. Consequently, use of agonist IS-Abs against each of these receptors has a different effect on the immune response and represents and alternative strategy to stimulate the immune attack against cancer.

One advantage of monoclonal antibodies as therapeutic drugs for use in treatment of patients is that vast amounts of these antibodies can be produced, simply because the cells producing these antibodies can be grown to very large numbers. A second advantage is that purification and storage of these antibodies is relatively simple. The third advantage is that these monoclonal antibodies look very similar to the antibodies that we humans have in considerable concentration in our blood. As a result, a dose of antibodies that is infused into the blood of a patient can remain active for quite a long time. In conclusion, antibodies represent a highly attractive drug format.