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Glycosylated, low antigenicity, low immunogenicity factor VIII

a low immunogenicity, low antigenicity technology, applied in the field of glycosylation, low antigenicity, low immunogenicity factor viii, can solve the problem of reducing the immunogenicity of the virus

Inactive Publication Date: 2005-01-13
LOLLAR JOHN S
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reduces the immunogenicity of the virus.

Method used

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Examples

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Embodiment Construction

As an example of the method used to create glycosylated, low antigenicity, low immunogenicity fVIII, we describe the introduction of a recognition site for N-linked glycosylation at leucine 486 within the A2 epitope. FVIII contains a serine at position 488 within the A2 epitope. The 486-488 sequence is leu-tyr-ser. Therefore, mutation of leucine to asparagine produces a sequence N-Y-S (using the single letter code), which is a recognition site for N-linked glycosylation.

This mutation was introduced by site-directed mutagenesis of the human B-domainless fVIII cDNA. The cDNA sequence corresponding to residues 484-508 is shown below. The DNA sequence is SEQ ID NO: 1; the translated, unmodified amino acid sequence is SEQ ID NO:2.

484     AACCGT CCT TTG TAT TCA AGG AGA TTA CCA AAAR   P   L   Y   S   R   R   L   P   K                                                        508GGT GTA AAA CAT TTG AAG GAT TTT CCA AAT CTG CCA GGA GAA ATAG   V   K   H   L   K   D   F   P   I   L   P   G   ...

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PUM

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Abstract

The development of inhibitory antibodies to blood coagulation factor VIII (fVIII) results in a severe bleeding tendency. These antibodies arise in patients with hemophilia A (hereditary fVIII deficiency) who have been transfused with fVIII. They also occur in non-hemophiliacs, which produces the condition acquired hemophilia. We describe a method to construct and express novel recombinant fVIII molecules which escape detection by existing inhibitory antibodies (low antigenicity fVIII) and which decrease the likelihood of developing inhibitory antibodies (low immunogenicity fVIII). In this method, fVIII is glycosylated at sites that are known to be antibody recognition sequences (epitopes). This produces the desired properties of low antigenicity fVIII and low immunogenicity fVIII. The mechanism is similar to one used by viruses such as the AIDS virus, which glycosylates its surface proteins to escape detection by the immune system.

Description

BACKGROUND OF THE INVENTION Hemophilia A is defined as hereditary deficiency of blood coagulation fVIII. FVIII is synthesized as a ˜300 kDa single chain protein with internal sequence homology that defines the “domain” sequence NH2-A1-A2-B-A3-C1-C2-COOH (FIG. 1) (Vehar et al. [1984]Nature 312:337-342). Domains are commonly delineated as A1 (Ala1-Arg372), A2 (Ser373-Arg740), B (Ser741-Arg1648), and A3-C1-C2 (Ser1690-Tyr2332) (Eaton et al. [1986]Biochem. 25:8343-8347). Despite its large size, the B domain of fVIII has no known function and can be deleted. FVIII is measured by its ability to correct the prolonged clotting time of plasma prepared from patients with hemophilia A. Hemophilia A, which is due to fVIII deficiency, is an X-linked, recessive disorder that is the most common severe, hereditary bleeding disorder in man. The mainstay of management of hemophilia A is fVIII replacement therapy by intravenous infusion. Current products in the marketplace include recombinant fVIII,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/755C12P21/00
CPCC07K14/755Y10S930/10C12P21/005
Inventor LOLLAR, JOHN S.
Owner LOLLAR JOHN S
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