Mammalian growth factor nucleic acids, vectors, and host cells

Details Mammalian growth factor nucleic acids, vectors, and host cells Mammalian growth factor nucleic acids, vectors, and host cells

1995-06-07

2002-08-13

Allen, Marianne P. (Department: 1631)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S320100, C435S252300, C435S252330, C435S357000, C435S365000, C536S023500

Reexamination Certificate

active

06432702

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains to a mammalian growth factor, pharmaceutical formulations comprising said factor and methods for healing wounds or burns in mammals comprising administering said formulations.
BACKGROUND OF THE INVENTION
This invention pertains to a novel polypeptide having mammalian growth factor activity and to methods for using it.
A variety of diffusible factors which stimulate the growth of cells in a hormone-like manner are generally called “growth factors”. Growth factors are often present in serum and have also been isolated from a variety of organs. They are protein molecules (or groups of such molecules) and in all known cases they interact with specific cell surface receptors to promote cellular growth and/or differentiation. Growth factors vary in their tissue specificity, i.e. some interact only with specific cell types, while others are active on a wider cell type range.
Among the best known groups of mammalian growth factors are: (1) platelet derived growth factor (PDGF), released from platelets; (2) epidermal growth factor (EGF); (3) hematopoietic growth factors (including interleukins 1, 2, and 3), required for growth and differentiation of lymphocytes, and colony stimulating factors (CSF), promoting growth and differentiation of hematopoietic stem cells; (4) angiogenic (literally “blood-vessel-forming”) growth factors, such as the fibroblast growth factors (FGF) believed to promote growth and organization of endothelial cells into new blood vessels; (5) miscellaneous growth factors released by tumor cells.
Two well-characterized angiogenic factors are basic and acidic fibroblast growth factors (FGF), believed to be most important in vivo for endothelial cell growth. However, neither basic FGF nor acidic FGF has proven useful as pharmaceutical agents for promotion of wound healing. Several factors may contribute to the unsuitability of basic FGF and acidic FGF as pharmaceutical agents. Neither factor is sufficiently stable for effective pharmaceutical formulation. Basic FGF demonstrates restricted interaction with FGF receptors in vitro, and thus cannot be expected to interact with all FGF receptors in vivo. Finally, basic FGF and acidic FGF have thus far proven ineffective in animal models.
Co-pending U.S. patent application Ser. No. 07/806,771 (abandoned) filed Dec. 6, 1991 discloses an angiogenic mammalian growth factor isolated from Kaposi's Sarcoma cells and having substantial homology to each of acidic and basic fibroblast growth factor in a single polypeptide. The growth factor protein comprises 176 amino acid residues and is a mature (secreted) glycoprotein. This growth factor has variously been called K-FGF or FGF-4, and it has shown promising results as a wound healing agent in preclinical studies in an ischemic rabbit ear model. In such a model, K-FGF promoted wound healing better than basic or acidic FGF.
Growth factors are believed to promote wound healing. For example, EGF present in saliva is believed to accelerate wound healing in mice. Schultz G. S et al. (
Science
232:350-352, 1986) report that transforming growth factor (TGF)-alpha and vaccinia virus growth factor (VGF), both of which are substantially homologous to EGF, accelerated epidermal wound healing in pigs when topically applied to second degree burns and were significantly more active than EGF.
Of the above-mentioned growth factors, the angiogenic growth factors would be particularly useful as wound healing agents because of their ability to promote the formation and growth of new blood vessels.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a novel growth factor useful as a wound healing agent in mammals.
Another object of the present invention is to provide a mammalian growth factor with increased biologic activities.
Yet another object of the present invention is to provide novel pharmaceutical formulations and methods for promoting wound healing in mammals.
A still further object of the present invention is to provide a truncated mammalian growth factor protein having substantial homology to each of acidic and basic fibroblast growth factor protein in a single polypeptide and having substantially higher specific activity than K-FGF protein.
SUMMARY OF THE INVENTION
The present invention pertains to a previously unknown form of truncated mammalian growth factor protein having substantial homology to each of basic and acidic fibroblast growth factor proteins in a single polypeptide chain, said truncated mammalian growth factor being substantially smaller than the full-length mammalian growth factor (the truncated protein is hereinafter referred to as truncated K-FGF or K-FGF-140).
In another aspect, the present invention provides a polypeptide having the amino acid sequence (SEQ. ID. NO. 1):
Ala Ala Val Gln Ser Gly Ala Gly Asp Tyr Leu Leu Gly Ile Lys Arg
  1               5                  10                  15

Leu Arg Arg Leu Tyr Cys Asn Val Gly Ile Gly Phe His Leu Gln Ala
             20                  25                  30

Leu Pro Asp Gly Arg Ile Gly Gly Ala His Ala Asp Thr Arg Asp Ser
         35                  40                  45

Leu Leu Glu Leu Ser Pro Val Glu Arg Gly Val Val Ser Ile Phe Gly
     50                  55                  60

Val Ala Ser Arg Phe Phe Val Ala Met Ser Ser Lys Gly Lys Leu Tyr
 65                  70                  75                  80

Gly Ser Pro Phe Phe Thr Asp Glu Cys Thr Phe Lys Glu Ile Leu Leu
                 85                  90                  95

Pro Asn Asn Tyr Asn Ala Tyr Glu Ser Tyr Lys Tyr Pro Gly Met Phe
            100                 105                 110

Ile Ala Leu Ser Lys Asn Gly Lys Thr Lys Lys Gly Asn Arg Val Ser
        115                 120                 125

Pro Thr Met Lys Val Thr His Phe Leu Pro Arg Leu.
    130                 135                 140
In yet another aspect, the present invention provides a pharmaceutical formulation for treating a mammal

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