Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Hormones – e.g. – prolactin – thymosin – growth factors – etc.
Reexamination Certificate
1991-10-04
2001-05-01
Kunz, Gary L. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Hormones, e.g., prolactin, thymosin, growth factors, etc.
C435S069700, C530S324000, C525S054100
Reexamination Certificate
active
06225449
ABSTRACT:
TECHNICAL FIELD
The invention relates to pharmaceutical compounds modified so as to extend their in vivo stability. More particularly, the invention concerns modifications of peptides of pharmaceutical significance by tandem extension with the carboxy terminal peptide of human chorionic gonadotropin.
BACKGROUND ART
PCT application WO90/09800, published Sep. 7, 1990, and incorporated herein by reference, describes various modifications of reproductive hormones. In addition, this publication discloses that protein pharmaceuticals and hormones in general may be modified to extend their biological half-lives in vivo by ligation of the carboxy terminal portion of the HCG-&bgr; subunit or a variant thereof to the carboxy terminus. The PCT application disclosure does not specifically address tandem extensions with multiple carboxy terminal portions (CTP) of the HCG-&bgr; chain. The present invention is directed to such tandem extensions.
Human chorionic gonadotropin (HCG) is one of at least four reproductive hormones in a family which also includes follicle stimulating hormone, luteinizing hormone, and thyroid stimulating hormone. All of these hormones are comprised of &agr; subunits which are identical among the group, and &bgr; subunits which differ according to the member of the family. The &bgr; subunit of HCG is substantially larger than that of the remaining three hormones in that it contains approximately
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additional amino acids at the C-terminus referred to herein as the carboxy terminal portion (CTP) which is considered responsible for the comparatively longer serum half-life of hCG as compared to other gonadotropins (Matzuk, M. et al.,
Endocrinol
(1989) 126:376). In the native hormone, this CTP extension contains four mucin-like O-linked oligosaccharides.
DISCLOSURE OF THE INVENTION
The invention provides modified peptides and proteins with extended biological half-lives which are characterized by containing, at their carboxy terminus, tandem extensions of at least two CTP sequences. These extended proteins are useful for the same biological functions as their unmodified forms, but permit reduced dosages and other advantages due to their extended biological half-life.
Thus, in one aspect, the invention is directed to a peptide or protein having a biological function in animals, wherein said peptide or protein is modified by a tandem extension at the C-terminus with at least two CTP units. In another aspect, the invention is directed to methods to extend the biological half-life of a peptide or a protein by providing such extensions. In other aspects, the invention is directed to recombinant materials and methods for the construction of the modified peptides of the invention, and to antibodies specifically immunoreactive with them.
REFERENCES:
patent: 4847325 (1989-07-01), Shadle et al.
patent: 5338835 (1994-08-01), Boime
patent: WO 85/01959 (1985-05-01), None
Fuad A. Fares et al., “Design of a long-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit,” Proceedings of the National Academy of Sciences of USA, vol. 89, No. 10, May 15, 1992, pp. 4304-4308.
“Polyclonal antibodies against the polypeptide and carbohydrate epitopes of recombinant human choriogonadotropin &agr;-subunit,” Molecular and Cellular Endocrinology, vol. 86, issued 1992, W. Chen et al.
“Protein engineering of antibody binding sites: Recovery of specific activity in an anti-digoxin single-chain Fv analogue produced inEscherichia coli,” Proc. Nat. Acad. Sci. USA, vol. 85, issued Aug. 1988, J.S. Huston et al.
Kunz Gary L.
Landsman Robert S.
Morrison & Foerster / LLP
Washington University
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