How we can improve haemophilia A treatment using shark antibodies!

Chances are you know someone who suffers from haemophilia A, but are you aware of how it impacts their everyday life? Hey! I’m Jakub, one of the Msci biochemistry students, and I’m here to tell you all about my project this year. I will be collaborating with Prof. John McVey in the hopes of improving treatment for haemophilia A. You may be asking yourself right now, “what is haemophilia A and why do we need to improve treatment for this disease?” Well, let me break it all down for you.

What is haemophilia A?

Haemophilia A is an inherited bleeding disorder occurring primarily in men (sorry lads), as it is linked to mutations in the X chromosome, unfortunately men only have one precious copy of chromosome X, thus a mutation in this copy will always result in change(1). The mutations which kindle the appearance of haemophilia A result in the absence or dysfunction of a crucial clotting protein named Factor VIII. Unfortunately, people which cannot produce functional factor VIII tend to experience uncontrolled bleeding episodes – which can be life threatening. Just the thought of this makes me uncomfortable, however for many people this is an everyday reality.

Figure 1: The inheritance model of haemophilia A (Author made). Haemophilia A carriers have a chance to pass on the defective copy of the X chromosome to their children. The inheritance of a defective X chromosome by male offspring will always result in symptoms due to the lack of a “backup” X chromosome (Male sex chromosomes XY, Female sex chromosomes XX).

The problem with current haemophilia A treatment

You will be grateful to hear that multiple treatment options for haemophilia A exist, and many new ones are being developed. Currently, the typical treatment regimen includes factor VIII replacement, during which patients inject themselves with lab-produced factor VIII intravenously. However effective this treatment may be, its biggest shortcoming is its inconvenience.

Just like many other proteins, factor VIII is degraded by several enzymes present in blood. In fact, its concentration will be halved every 8-12 hours (meaning it has a half-life of 8-12 hours). I know this may seem like a long time at first glance, however this half-life means patients need to inject themselves with factor VIII at least once every other day to maintain a functional dose of the protein. The needles which are used for factor VIII injections are thick, as relatively high volumes of the treatment solution need to be administered to the patient to be therapeutically effective. The frequent injections of high FVIII volumes can be unpleasant to say the least and really impact the quality of life of haemophilia A sufferers.

Numerous attempts have been made to increase the half-life of factor VIII in the last few years, with the goal to reduce injection frequency and improve patient quality of life, unfortunately most of them fall short as they only increase the half-life of factor VIII by approximately 4 hours, which does not solve the problem of frequent injections. This has been attributed to factor VIII tethering itself to another important clotting protein, called von Willebrand factor (vWF). vWF only has a half-life of 16 hours, and when FVIII is tethered to vWF, the duet is degraded simultaneously(2). You could say, a chain is only as strong as its weakest link; in this case, even if we substantially improve the half-life of factor VIII it will only be held back by vWF.

The solution to the problem!

So, what can we do? The approach being undertaken by the McVey lab aims to remove the unfruitful interaction between factor VIII and vWF by very slightly altering the structure of factor VIII. At this point you may be asking yourself, “so where does this famed shark antibody come in, and what is so special about it!?” First of all, antibodies are proteins generated by cells of the immune system, they can robustly and selectively adhere to specific regions of a protein.

Figure 2: Comic depicting antibody function (Author made). Antibodies can selectively bind to specific locations termed antigens on a protein.

The modified factor VIII will incorporate a shark antibody in its structure, which will strongly tether it to another protein in the blood, replacing the interaction of factor VIII and vWF with a more lucrative interaction, aiming to extend the half-life of factor VIII from a meagre 12 hours to a whopping 20 days! Let me further quench your thirst for shark antibody knowledge by telling you that this antibody is particularly useful as it is much smaller than a conventional human antibody(3). This characteristic makes its inclusion in our modified factor VIII less disruptive in terms of structure, helping to preserve proper functioning of factor VIII.

The overall result of this modified factor VIII would be longer half-life of the protein, and a longer half-life means less frequent injections and improved quality of life for haemophilia A sufferers. Anyway, that’s it for now, hopefully you’ve enjoyed reading my blog post as much as I enjoyed writing it and learned something along the way. Until next time – Jakub.

References

  1. National Hemophilia Foundation. (n.d.). Hemophilia A. [online] Available at: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A [Accessed 26 Nov. 2019].
  2. Pipe S.W., Montgomery R.R., Pratt K.P., Lenting P.J. & Lillicrap D. (2016) ‘Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for haemophilia A’ blood, 128(16), pp. 2007-16
  3. Kovaleva M., Ferguson L., Steven J., Porter A. & Barelle C. (2014) ‘Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development’ Expert opinion on biological therapy, 14(10) pp. 1527-39