Catalytic Antibodies (Abzymes)
As the name suggests, abzyme means antibody behaving like an enzyme. It is also called catmab or catalytic monoclonal antibody. We know that antibody binds to the target antigen or pathogens and then activates the complement system, phagocytosis, and other processes to eliminate the pathogen. In contrast, the enzymes are the catalysts that drive a reaction by stabilizing its transition state, decreasing the activation energy, and allowing for a more rapid conversion of substrate to product. (Fig 1).
So, scientists thought, why not combine the actions of an antibody and an enzyme and make a substance that catches hold of the antigen, analogous to the function of an antibody and neutralizes antigen on its own, similar to the function of enzymes. So this is how the idea of combining the functions of antibodies and enzymes to create abzymes was born.
Production of abzymes
Suppose an antibody is developed to bind to a molecule that is structurally similar to the transition state of a given chemical reaction. In that case, the developed antibody will bind to and stabilize the transition state, just like a natural enzyme, by lowering the activation energy of the reaction, thus catalyzing the reaction. Therefore, raising an antibody to bind to a stable transition-state analog can produce a new and unique type of antibody behaving like an enzyme.
Let’s take an example of generating abzymes that can undergo ester hydrolysis. For this, the hapten-carrier complex is synthesized in which hapten structurally resembles the transition state of an ester undergoing hydrolysis (Fig 2). Then the mice are immunized with this hapten-carrier complex, generating antibody-producing plasma cells, which are then fused with myeloma cells to yield hybridoma cells. These hybridoma cells can produce anti-hapten monoclonal antibodies.
When these anti-hapten monoclonal antibodies are incubated with an ester substrate, they can accelerate the hydrolysis of the ester substrate, thus behaving like enzymes (Fig 3).
The catalytic activity of abzymes is highly specific as they hydrolyze only those esters whose transition state structure resembles that of the transition state analog used as a hapten. Thus, the abzymes can be generated that cut peptide bonds at specific amino acid residues like the restriction enzymes that cut DNA at specific nucleotides. Antibodies have exceptional specificity and high affinity, so combining this with catalytic activity seems like a perfect combination.
Applications of abzymes
There are potential clinical applications of abzymes like:
- Abzymes can prevent cells from getting infected by HIV. They have been developed to hydrolyze the antigenic region of protein gp102 of HIV, which is the CD4 binding site of the HIV (Fig 4). The hydrolysis of gp102 prevents the virus from binding to the CD4 protein present on the target cells like T helper cells. Thus the virus becomes inert and is unable to infect its target cells.
- In cancer treatment, one of the major obstacles is that the cytotoxic drugs destroy both the normal and cancer cells. Hence there is a need for specific targeting of cancer cells and subsequent prodrug activation, which then destroys the oncogenic cells. Abzymes can be used in the treatment of cancer. They are the therapeutic agents that function as homing devices for the site-specific delivery of the prodrug and then activating the prodrug into the active anti-cancer drug (Fig 5). One out of the two sites of a monoclonal antibody acts as an antigen-binding site on the cancer cell, while the other site serves as an abzyme to activate the anti-cancer drug.
The prodrug is a pharmacologically inactive compound converted into an active form by endogenous enzymes or metabolism (Fig 6). Here, the abzyme can activate the prodrug into the active cytotoxic form of the drug, which in turn can potentially kill the target cancer cells.
