Team:CU-Boulder/Description

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Problem

Monoclonal antibody therapies have become popular in pharmaceutics due to being effective against many types of autoimmune diseases including cancer. Though these therapies are very useful they can sometimes cause the immune system to become overactive. If a patient's immune system becomes overactive the antibodies cannot be flushed out of the system fast enough due to having a half life on the order of weeks. By the time the destructive antibodies are flushed out of the system it may be too late for the patient.

Our Solution

Our solution to this issue of the immune system becoming overactive is to engineer a switch mechanism into the antibodies. Our antibody is engineered to be activated and deactivated by the addition and removal of the small molecule rapamycin. Rapamycin has a half life on the order of hours so removing the rapamycin from the body is much faster than removing the antibodies.

The Antibody

An antibody, also called immunoglobublin, is a protein produced by the immune system in response to a foreign invader called an antigen. An antibody will bind to the antigen and cause an immune response to remove the foreign invader.

An antibody is a "Y" shaped protein that is composed of a light and heavy chain. Each chain is made up of immunoglobulin subunits. The antibody is composed of two regions: the constant and variable regions. The variable region consists of the top parts of the "Y" and are unique to the type of antibody. The variable region is the region that binds to the antigen. The rest of the antibody is the constant region.

The antibody we chose to use binds to antigen PD1(Programmed Cell Death protein 1). PD1 is a immunosuppressant that suppresses T-Cells and can prevent autoimmune diseases. The antibody is the Fab(top "Y" regions) of pembrolizumab

Rapamycin

Rapamycin is a small molecule that acts as an immunosuppressant and possible cancer treatment. The small molecule can bind to two different protein FKBP12 and the rapamycin binding domain of mTor,FRB. Originally the FKBP12 protein is disordered. When rapamycin binds to it the FKBP12 becomes ordered and the FKBP12-rapamycin complex is able to bind the FRB protein.

Provided by Science Direct

Together

For our project we replaced the bottom two immioglobulin subunits with the rapamycin complex. This allows our antibody to be turned on and off with and without the presence of rapamycin. The top variable region of the antibody is called an scfv (single chain fragment variable) and must have a long linker to make the two halves of the variable region stay together and bind to the antigen. Without the linker between the two halves of the variable region, the variable region will not stay together and won't bind the antigen. This is what sparked our idea to create a linker with the rapamycin complex that could link and unlink the two variable regions making the variable regions active and inactive.

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