Plenge Lab
Date posted: February 14, 2016 | Author: | No Comments »

Categories: Drug Discovery Immunogenomics


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. While autoantibodies were the key to understanding acquired TTP pathogenesis, human genetics contributed, too, as rare mutations in ADAMTS13 cause familial TTP (link here).

But if ADAMTS13 deficiency leads to TTP, and plasma exchange treats TTP, then therapeutic intervention is ADAMTS13 replacement. In drug discovery, it is often easier to therapeutically inhibit a target or pathway, rather than activate it.

Enter caplacizumab, an anti–von Willebrand factor humanized nanobody. The nanobody does not replace ADAMTS13, but rather blocks the downstream consequence of ADAMTS13 deficiency, the binding of von Willebrand factor to platelets. The NEJM study showed that this therapeutic intervention results in a more rapid resolution of TTP episodes.

In a broader context, the reason I like this story is that it highlights the importance of dissecting the human immune system for new targets and pathways in drug discovery. What is cool (no pun intended) is that new genomic technologies are now available to study the human immune system in exquisite detail – for example, identification of antigens that drive the human immune response. Neutralizing antibodies have been identified that recognized the hemagglutinin glycoprotein antigen from influenza A virus (here). Such information is being used to develop therapies that provide passive protection against influenza infection, as well as to inform universal vaccine design. Another autoantibody example is in narcolepsy, where autoimmune-destruction of specific neurons in the brain of identified orexin as a therapeutic target for sleep (here).

The coldest day of my life? That was in January 1994 when I was in medical school at Case Western Reserve University (CWRU) in Cleveland, OH. On that -22 F° day, I debated whether to take a year off to pursue genetics research as part of a Howard Hughes Fellowship in the laboratory of Hunt Willard. The decision I made on that frigid day changed my life, as it introduced me to a scientific field, human genetics, which has guided most of my scientific career over the past 22 years.


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