Autoantibodies as experiments of nature for drug discovery | example in NEJM on thrombotic thrombocytopenic purpura (TTP)
Today was the second coldest day of my life. When I woke up in Ludlow, Vermont, it was -20 degrees Fahrenheit; with wind chill it was -45° F. As the kids played downstairs, I caught up on my reading comforted by a raging log fire.
The topic de jour: non-genetic examples of causal human biology for drug discovery. Here, the experiment of nature was the formation of autoantibodies against a target and pathway implicated in acquired thrombotic thrombocytopenic purpura (TTP), a life-threatening disorder.
The study that caught my interest, “Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura”, was published last week in the New England Journal of Medicine. I won’t say much about the NEJM article itself, but I will briefly discuss the background leading up to the clinical trial. The key point: autoantibodies against ADAMTS13 pinpointed the target and pathway as causal in the ideal model organism, humans.
The story starts in 1976, when whole blood exchange transfusion resulted in clinical benefit in 8 of 14 patients with TTP. The following year, it was determined that the plasma fraction of the blood was the source of clinical benefit. It took approximately 20 years, however, to identify the deficient plasma factor as ADAMTS13, with deficiency caused by IgG autoantibodies that inhibit the enzyme.…