Abstract
Hemophilia A is a hereditary bleeding disorder resulting from reduced factor FVIII activity. It occurred in 1/5000 male. Currently, the treatment option is with the factor FVIII replacement therapy. A long-acting recombinant monomeric FVIII-Fc fusion protein product (Eloctate®) has been approved in 2014 by the US FDA, it requires to infuse the drug for every 3 days or twice a week. There is a clinical need to develop longer half-life product to extend the treatment option to once a week infuse for hemophilia A patients. Recently, we have developed a dimeric recombinant factor VIII-Fc (drFVIII-Fc) fusion protein therapeutic candidate, which is entering the clinical development in China. To generate a longer half-life recombinant FVIII product, we have developed a PEGylation method to PEGylated this drFVIII-Fc fusion protein to PEGdrFVIII-Fc. We have analyzed and characterized the fusion protein by various analytic methods, as well as in vivo animal tests. It was shown that PEGdrFVIII-Fc fusion protein has been modified with about five Y type of 40kd PEG; the remaining activity is around 700 IU/mg, and the in vivo tests in cynomolgus monkey demonstrated that the fusion protein has a half-life of about 37 hours. The data also showed that there was no detectable affinity binding activity of vWF to a PEGdrFVIII-Fc fusion protein, as compared with the binding activity of 5.16X10-4M for the molecule of a drFVIII-Fc fusion protein. In conclusion, we are able to generate a PEGylated form of a drFVIII-Fc molecule with the relevant specific activity and has been shown the molecule with the prolonger half-life in the in vivo tests. The further biochemical analysis demonstrated PEGdrFVIII-Fc fusion protein with no detectable vWF binding activity, which might explain why its half-life is longer than vWF's ~15hours half-life in vivo. This molecule is likely to be used as a once-weekly treatment option for hemophilia A patients. Currently, we are in the development stage of an IND filing in China.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
![](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/132/supplement%201/10.1182_blood-2018-99-112030/1/m_inf01.gif?Expires=1722751644&Signature=soBwMYyrWxfUCckbxOcnZkV2OOSM11-bI70jWwqYA3hdQIpff3Iz7eWKnRAmrGH7d48~ceu~yRwB-XNePtSXmh9Q7B8TvJxKAPKCyPKHebhqMtXtKopj7hMeQEq-A4lxT7BM3lVPrY-YzVA3r5NrcVeQon9j1KUzVgNDs6ZyvrZ2JHusLIDgy3ttpZvjwrsNXwTlRdeo1-fAsE3Xt11uZR7OmbR9p1YzL-agEZNpbmnkv4M4ltVbZfQD2KAXpjQmG0cEYUOQQit2rimiPDiacqFc170rsLMmUXMe4r3GDmjNL4cQsiasyI1UJDD2WtNqqhxs-kB0ymB1N9iH4NNeJQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
This icon denotes a clinically relevant abstract
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal