Richard Lerner (Scripps Research Institute)
Researchers at Scripps Research Institute in La Jolla, California and Scripps Korea Antibody Institute developed a new process to more rapidly identify antibodies that target specific disease molecules. The team from the lab of Richard Lerner, an immunochemistry professor at and former director of Scripps, published its findings yesterday in the journal Chemistry & Biology (paid subscription required).
Antibodies are the basis of wide range of medicines and disease diagnostics, which bind to distinct molecular targets. They are proteins produced by B cells, a type of lymphocyte or immune cell, that are programmed to mutate a small set of genes in response to attacking microorganisms, such as bacteria or viruses.
Earlier research by Lerner and colleagues devised techniques to identify potential B cells for generating antibodies from large libraries of prospects, then determine which of the prospects can bind to the desired targets. Those techniques have since been used to identify therapies now on the market.
Their methods for identifying potential B cell antibodies were further refined in a process published last year that not only pointed out antibodies that bind to specific targets, but also perform desired functions after binding, such as activating receptors on the target cells. In that study, the Scripps team demonstrated the process by identifying an agonist — a molecule that acts like an antibody — of the hormone erythropoietin that stimulates production of red blood cells.
While a key development, the refined identification process still took a great deal of time. The technique measures the proliferation of cells, an indirect method the researchers say is very slow, and returns results only applicable to that specific, targeted biological pathway. Hongkai Zhang, a research associate in Lerner’s lab and first author of the new study, says the new study aimed to find a more direct method for identifying antibodies that would also be more generalizable to other antibiody functions.
To meet this need, the Scripps team devised a process for fluorescing indicators of molecular activity called reporter cells that light up when an antibody activates a target receptor, which the researchers say can be applied to any signalling pathway. In addition, each test cell in the system produces a unique antibody that works specifically on that cell.
The researchers employed an automated system that maintains millions of these cultured cells, and can quickly deliver test viruses to generate their unique antibodies. The system then detects the fluorescing genes indicating a match with the target molecule. The Scripps team says the technique can screen two million test cells per hour.
To test the technique, the Scripps researchers applied their methods to finding an agonist for thrombopoietin, a hormone controlling production of platelets essential for effective clotting of blood for healing wounds, but also for patients in chemotherapy who experience lower platelet production. Clinical trials of an engineered form of thrombopoietin in 2001, say the researchers, showed it induced an antibody response that resulted in giving patients lower platelet counts, the exact opposite of the intended effect.
Using their antibody identification process, the Scripps team found an antibody, labeled 3D9, that activated the thrombopoietin receptor in smaller quantities than thrombopoietin itself, which the researchers attribute to the antibody being a larger and more stable protein molecule than the small-molecule original. Zhang tested 3D9 in mice, and found after eight days, a single dose of the antibody tripled platelet counts, a more potent response than the engineered form of thrombopoietin.
While other thrombopoietin agonists have come on the market since the trials of the engineered variety, Lerner says there’s a real need for thrombopoietin agonists that do not look like the natural form. A pharmaceutical company, reports the institute, apparently agrees with Lerner and already licensed the antibody from Scripps for development.
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