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. 2021 Nov;19(11):2710-2725.
doi: 10.1111/jth.15480. Epub 2021 Aug 17.

Increased potency of recombinant VWF D'D3 albumin fusion proteins engineered for enhanced affinity for coagulation factor VIII

Jenny Chia  1 , Sabine Pestel  2 , Isabelle Glauser  1 , Kerstin Emmrich  1 , Matthew P Hardy  1 , Marcel Mischnik  2 , Elmar Raquet  2 , Vesna Tomasetig  1 , Philipp Claar  2 , Anton Zalewski  1 , Gregory T Bass  1 , Victor Turnbull  1 , Chao-Guang Chen  1 , Michael J Wilson  1 , Con Panousis  1 , Thomas Weimer  2 , Arna Andrews  1 , Anne M Verhagen  1 , Steve K Dower  1
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Free article

Increased potency of recombinant VWF D'D3 albumin fusion proteins engineered for enhanced affinity for coagulation factor VIII

Jenny Chia et al. J Thromb Haemost. 2021 Nov.
Free article

Abstract

Background: We have recently reported on a recombinant von Willebrand factor (VWF) D'D3 albumin fusion protein (rD'D3-FP) developed to extend the half-life of coagulation factor VIII (FVIII) for the treatment of hemophilia A. Based on predictive modelling presented in this study, we hypothesized that modifying rD'D3-FP to improve FVIII interaction would reduce exchange with endogenous VWF and provide additional FVIII half-life benefit.

Objectives: The aim of this study was to identify novel rD'D3-FP variants with enhanced therapeutic efficacy in extending FVIII half-life.

Methods: Through both directed mutagenesis and random mutagenesis using a novel mammalian display platform, we identified novel rD'D3-FP variants with increased affinity for FVIII (rVIII-SingleChain) under both neutral and acidic conditions and assessed their ability to extend FVIII half-life in vitro and in vivo.

Results: In rat preclinical studies, rD'D3-FP variants with increased affinity for FVIII displayed enhanced potency, with reduced dose levels required to achieve equivalent rVIII-SingleChain half-life extension. In cell-based imaging studies in vitro, we also demonstrated reduced dissociation of rVIII-SingleChain from the rD'D3-FP variants within acidic endosomes and more efficient co-recycling of the rD'D3-FP/rVIII-SingleChain complex via the FcRn recycling system.

Conclusions: In summary, at potential clinical doses, the rD'D3-FP variants provide marked benefits with respect to dose levels and half-life extension of co-administered FVIII, supporting their development for use in the treatment of hemophilia A.

Keywords: coagulation factor VIII; hemophilia A; pharmacokinetics; recombinant fusion proteins; von Willebrand factor.

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References

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