The Antibody Arsenal: More Complex Targeted Agents Primed for Increased Potency
Published Online: Tuesday, August 6, 2013
Although antibodies have yet to meet their full potential as single anticancer agents, new technologies for engineering improved antibody structures are paving the way for further success. Here, we provide a short guide to the past, present, and future of anticancer antibody therapy.
A Hat Trick of Nobel PrizesAntibodies, or immunoglobulins (Igs), are proteins found in bodily fluids, produced by the B cells of the immune system, which coordinate immune responses against foreign substances. Each has a unique target (an antigen) that it recognizes on the surface of the foreign cell to which it binds, and then recruits other components of the immune system to destroy the cell.
Igs exist in five different forms—IgA, IgD, IgE, IgG, and IgM—that differ in their biological properties, functions, and location in the body. IgG is the predominant form in the blood and is composed of two identical light chains and two identical heavy chains, which are connected to form the distinctive Y-shaped molecule described by Rodney R. Porter and Gerald M. Edelman, who won a Nobel Prize for deciphering the structure of an antibody in 1972.
The protein chains found in the stem of the Y are very consistent in their composition, and this part of the antibody contains the fragment crystallizable (Fc) region, which engages and activates the effector cells of the immune system. Conversely, the protein chains in the two “arms” of the Y vary widely. This is known as the variable fragment (Fv) region and contains the two fragment antigen-binding (Fab) domains that determine which antigen the antibody binds.
Each B cell produces a specific antibody that recognizes a small part of a specific antigen. When they encounter their target antigen, they ramp up antibody production by creating an army of clones that are all secreting the same antibody. Since they are derived from a single B cell, these antibodies are referred to as monoclonal antibodies (mAbs).
Many researchers recognized the huge therapeutic potential of mAbs. The German scientist Paul Ehrlich, whose work in immunology was recognized with a Nobel Prize in 1908, famously dubbed them as “magic bullets” due to their ability to seek out and destroy specific toxins.
The third Nobel Prize-winning discovery came in the 1970s when César Milstein and Georges J.F. Köhler described the hybridoma technique, which allowed fusion of immortal myeloma cells to antibody-producing B cells taken from the spleen of a mouse immunized against a specific antigen. As a result of this advance, it became possible to produce large amounts of specific mAbs in the laboratory, thus spawning an explosion in antibody research as scientists were able to make mAbs directed against the antigen of their choice.
Early therapeutic antibodies met with limited success, mostly because they were produced in mouse cells, and therefore induced an immune response in a human host and were rapidly cleared from the body before they could do any good. To overcome these limitations, chimeric and humanized antibodies were developed, with a mixture of mouse and human components that are approximately 65% and 95% human, respectively. Finally, the ability to transfer human genes into the mouse genome to generate transgenic mice enabled the production of fully human antibodies.
Nowadays, therapeutic antibodies are typically produced using mammalian cell lines, which allow much larger-scale production. Chinese hamster ovary (CHO) cells are the most common cell line used, with 10 of the 13 approved anticancer antibodies made in CHO cells. Currently, antibodies are created in large bioreactors, with production levels in excess of 10g/L. However, recent research has shown that yeast and algae could be used in the future to generate therapeutic proteins like antibodies much more quickly and at a fraction of the cost.
Antibodies as Anticancer AgentsmAbs make ideal anticancer agents because they have the potential to specifically target tumor cells for destruction while sparing normal cells, thereby overcoming the significant toxicities associated with traditional cancer therapies.
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