A FULLY HUMAN BISPECIFIC ANTIBODY FUNCTIONALLY RESCUES FACTOR VIII DEFICIENCY EX VIVO
Author(s): ,
Wei Wang
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
John Blackwood
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Roberto Magliozzi
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Leonardo Moraes
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Alessandro Sinopoli
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Bertie Chi
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Chris Sellick
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Claire Pearce
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Igor Theurl
Affiliations:
Kymab Ltd,Cambridge,United Kingdom;Medical University of Innsbruck,Innsbruck,Austria
,
Jeffrey Hollins
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Karen Dickson
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
,
Allan Bradley
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
E-Chiang Lee
Affiliations:
Kymab Ltd,Cambridge,United Kingdom
EHA Library. Wang W. Jun 15, 2019; 267434; S851
Wei Wang
Wei Wang
Contributions
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Abstract

Abstract: S851

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 12:30 - 12:45

Location: Hall 3B

Background

Haemophilia A is caused by deficiency of Factor VIII (F.VIII), an essential blood-clotting cofactor. Prophylaxis or on-demand treatment with recombinant FVIII forms the current standard of care to prevent bleeding in Haemophilia A patients in the developed world. However, approximately 30% of severe haemophilia A patients develop inhibitory antibodies against F.VIII. Moreover, FVIII treatment requires venous access which is burdensome. The recent successful clinical trials and subsequent regulatory approval of a F.VIII-mimetic bispecific antibody, Hemlibra, in Haemophilia A patients with inhibitors have provided much needed hope for suffers and their family. However, whilst Hemilibra represents a major breakthrough in the field, there remain some concerns about balancing the risks of bleeding with those of thrombosis when using this agent.

Aims
To develop a new fully human FVIII mimetic bispecific antibody that can support the assembly of a functional Factor IXa (F.IXa) and Factor X (F.X) complex, thereby replacing F.VIII function in vivo.

Methods
Using Kymab’s bispecific antibody platform, we developed KY1049, a fully human common light chain (CLC) bispecific antibody, to test as an effective functional mimetic of F.VIII. KY1049 bispecific heterodimer was purified using standard Protein A chromatography, followed by cation ion exchange chromatography (cIEX). The mass and heterodimer purity of the bispecific molecule was confirmed using Mass Spectrometry (MS). A combination of in vitro and ex vivo assays was used to characterize the cIEX purified bispecific antibody, including chromogenic FXase and Activated Partial Thromboplastin Time (aPTT). The affinities of the FIX arm and FX arm of KY1049 bispecific to FIX and FX, respectively, were determined using Surface Plasmon Resonance (SPR).

Results
cIEX purified KY1049 molecule was confirmed as a single species by MS. After denaturing, the molecular weights of the two heavy chains and one light chain matches in silico predicted molecular weights. Purified KY1049 actively generated activated F.X (F.Xa) and functionally rescued the clotting defect in F.VIII-depleted plasma in the aPTT assay. Importantly, ex vivo activities of KY1049 indicates its therapeutic benefit is likely to be similar in efficacy to Hemlibra. KY1049 binds F.IX and F.X simultaneously by SPR, but the affinities are different from those reported of Hemlibra.

Conclusion

We have developed KY1049, a FVIII mimetic bispecific antibody, that demonstrates biological activities comparable to those reported for Hemlibra.  Its therapeutic benefit is likely to be at least as effective as Hemlibra. Furthermore, initial analysis of the KY1049 molecule also showed some differences between the two molecules which could be harnessed to enhance its physical properties and activity.

Session topic: 33. Bleeding disorders (congenital and acquired)

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