7AHU

Anti-FX Fab of mim8 in complex with human FXa


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.214 

Starting Models: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A factor VIIIa-mimetic bispecific antibody, Mim8, ameliorates bleeding upon severe vascular challenge in hemophilia A mice.

Ostergaard, H.Lund, J.Greisen, P.J.Kjellev, S.Henriksen, A.Lorenzen, N.Johansson, E.Roder, G.Rasch, M.G.Johnsen, L.B.Egebjerg, T.Lund, S.Rahbek-Nielsen, H.Gandhi, P.S.Lamberth, K.Loftager, M.Andersen, L.M.Bonde, A.C.Stavenuiter, F.Madsen, D.E.Li, X.Holm, T.L.Ley, C.D.Thygesen, P.Zhu, H.Zhou, R.Thorn, K.Yang, Z.Hermit, M.B.Bjelke, J.R.Hansen, B.G.Hilden, I.

(2021) Blood 138: 1258-1268

  • DOI: https://doi.org/10.1182/blood.2020010331
  • Primary Citation of Related Structures:  
    7AHU, 7AHV

  • PubMed Abstract: 

    Hemophilia A is a bleeding disorder resulting from deficient factor VIII (FVIII), which normally functions as a cofactor to activated factor IX (FIXa) that facilitates activation of factor X (FX). To mimic this property in a bispecific antibody format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting bispecific antibody (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant of 16 nM. Binding affinity with FIXa and FX in solution was much lower, with equilibrium dissociation constant values for FIXa and FX of 2.3 and 1.5 µM, respectively. In addition, the activity of Mim8 was dependent on stimulatory activity contributed by the anti-FIXa arm, which enhanced the proteolytic activity of FIXa by 4 orders of magnitude. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation, with potencies 13 and 18 times higher than a sequence-identical analogue of emicizumab. A similar potency difference was observed in a tail vein transection model in hemophilia A mice, whereas reduction of bleeding in a severe tail-clip model was observed only for Mim8. Furthermore, the pharmacokinetic parameters of Mim8 were investigated and a half-life of 14 days shown in cynomolgus monkeys. In conclusion, Mim8 is an activated FVIII mimetic with a potent and efficacious hemostatic effect based on preclinical data.


  • Organizational Affiliation

    Global Drug Discovery and.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-FX Fab of mim8 light chainA [auth L],
C [auth A]
216Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-FX Fab of mim8 heavy chainB [auth H],
D [auth B]
222Homo sapiensMutation(s): 0 
Entity Groups  
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XE [auth C],
G [auth E]
241Homo sapiensMutation(s): 0 
Gene Names: F10
EC: 3.4.21.6
UniProt & NIH Common Fund Data Resources
Find proteins for P00742 (Homo sapiens)
Explore P00742 
Go to UniProtKB:  P00742
PHAROS:  P00742
GTEx:  ENSG00000126218 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00742
Sequence Annotations
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XF [auth D],
H [auth F]
58Homo sapiensMutation(s): 0 
Gene Names: F10
EC: 3.4.21.6
UniProt & NIH Common Fund Data Resources
Find proteins for P00742 (Homo sapiens)
Explore P00742 
Go to UniProtKB:  P00742
PHAROS:  P00742
GTEx:  ENSG00000126218 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00742
Sequence Annotations
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  • Reference Sequence
Biologically Interesting Molecules (External Reference) 1 Unique
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.214 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.13α = 90
b = 105.25β = 89.995
c = 145.78γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2021-07-07
    Type: Initial release
  • Version 1.1: 2021-10-20
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Refinement description