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Interferon-alpha polypeptides and conjugates

a polypeptide and interferon-alpha technology, applied in the field of polypeptides, can solve the problems of short serum half-lives, high rate of chronic infection, and inability to optimize use as pharmaceuticals, and achieve the effect of reducing the number of copies of a virus

Inactive Publication Date: 2007-01-25
MAXYGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018] In another aspect, the invention provides a method of inhibiting viral replication in virus-infected cells, the method comprising contacting the virus-infected cells with a polypeptide or a conjugate of the invention. The invention also provides a method of reducing the number of copies of a virus in virus-infected cells, comprising contacting the virus-infected cells with a polypeptide or a conjugate of the invention.

Problems solved by technology

Although these proteins possess therapeutic value in the treatment of a number of diseases, they have not been optimized for use as pharmaceuticals.
For example, dose-limiting toxicity, receptor cross-reactivity, and short serum half-lives significantly reduce the clinical utility of many of these cytokines (Dusheiko, G.
As a likely consequence of this genetic diversity and active inhibition of the antiviral response, HCV (particularly Genotype 1) has the ability to escape the host's immune surveillance, leading to a high rate of chronic infection.

Method used

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  • Interferon-alpha polypeptides and conjugates
  • Interferon-alpha polypeptides and conjugates
  • Interferon-alpha polypeptides and conjugates

Examples

Experimental program
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Effect test

example 1

Determination of Surface-Accessible Residues of Interferon-Alphas

Surface Exposure of Human Interferon-α2a Residues:

[0567] Based on the 24 NMR structures of human interferon-alpha 2a reported by Klaus et al., J. Mol. Biol., 274: 661-675 (1997), the fractional ASA of side chains was calculated. The sequence numbering used below is based on the mature sequence of the human interferon-alpha 2a protein (identified herein as SEQ ID NO:47). It is noted that this structure contains two disulphide bridges involving Cys1-Cys98 and Cys29-Cys138, respectively. By computing the ASA and the fractional ASA and taking the average of the 24 structures, focusing on the ASA of the side chains, it was determined that the following residues have more than 25% fractional ASA: D2, L3, P4, Q5, T6, H7, S8, L9, G10, R12, R13, M16, A19, Q20, R22, 23, I24, S25, L26, F27, S28, L30, K31, R33, H34, D35, G37, Q40, E41, E42, G44, N45, Q46, Q48, K49, A50, E51, E58, Q61, Q62, N65, S68, T69, K70, D71, S73, A74, D77...

example 2

Antiviral Activites of Interferon-Alpha Polypeptides

[0572] Patients with chronic HCV infection have initial viral loads in the range of 104-107 copies of HCV RNA / ml. Upon treatment with IFN-alpha, the viral load characteristically undergoes two distinct log-linear phases of decline reflecting two distinct mechanisms (FIG. 1B). The initial drop in viral load occurs in about the first two days and is believed to be due to the reduction in rate of virus production by infected liver cells in the face of the IFN-alpha therapy.

[0573] The major technical challenge with HCV is that the virus cannot be grown in vitro and has only recently been cultured in tractable animal models. There are, however, viruses that replicate in vitro which are considered to be useful surrogates for HCV viral replication. In vitro surrogate assays believed to be predictive of in vivo HCV antiviral activity include the assays described in the Materials and Methods section above, which measure the ability of tes...

example 3

TH1 ACTIVITES of Interferon-Alpha Polypeptides

[0575] The TH1 assay was designed to monitor the enhancement of differentiation of naïve T cells into TH1 cells by IFN-alpha as determined by the amount of IFN-gamma detected in the culture supernatants. Table 8 provides relative TH1 activities of various IFN-alpha polypeptides assayed as described in the Materials and Methods section above.

TABLE 8Fold overSampleSEQ ID NOIFN-alpha 2a14Epi18SEQ ID NO: 13>30x25Epi19SEQ ID NO: 38>30xIFN-alpha Con1SEQ ID NO: 5810x to 15xIFN-alpha 2aSEQ ID NO: 471 (ref)

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Abstract

The present invention provides interferon-alpha polypeptides and conjugates, and nucleic acids encoding the polypeptides. The invention also includes compositions comprising these polypeptides, conjugates, and nucleic acids; cells containing or expressing the polypeptides, conjugates, and nucleic acids; methods of making the polypeptides, conjugates, and nucleic acids; and methods of using the polypeptides, conjugates, and nucleic acids.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] Pursuant to 35 U.S.C. §119(e), this application claims the benefit of U.S. Provisional Application Ser. No. 60 / 572,504 filed on May 19, 2004, the disclosure of which is incorporated by reference herein in its entirety for all purposes.FIELD OF THE INVENTION [0002] The present invention relates generally to polynucleotides and polypeptides encoded therefrom, conjugates of the polypeptides, as well as vectors, cells, antibodies, and methods for using and producing the polynucleotides, polypeptides, and conjugates. BACKGROUND OF THE INVENTION [0003] Interferon-alphas are members of the diverse helical-bundle superfamily of cytokine genes (Sprang, S. R. et al. (1993) Curr. Opin. Struct. Biol. 3:815-827). The human interferon-alphas are encoded by a family of over 20 tandemly duplicated nonallelic genes and psuedogenes that share 85-98% sequence identity at the amino acid level (Henco, K. et al. (1985) J. Mol. Biol. 185:227-260). Genes which...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/56C07H21/04C12P21/04A61K38/21A61K47/48C07K14/555C12P21/02C12Q1/68
CPCA61K38/212C07K14/56A61K47/48215A61K47/60A61P31/12A61P31/14A61P31/18A61P31/20A61P43/00Y02A50/30
Inventor PATTEN, PHILLIP A.VISWANATHAN, SRIDHARNISSEN, TORBEN LAUESGAARDVOGT, ANNEKROPSHOFER, HARALDSCHUMACHER, RALFFISCHER, STEPHANSEEBER, STEFANGROSSMANN, ADELBERTHESSE, FRIEDERIKESCHAUBMAR, ANDREASFALKENSTEIN, ROBERTOKOLL, HANSDEMBOWSKI, MARKUS
Owner MAXYGEN
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