Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-08-15
2001-04-03
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S069100, C530S399000
Reexamination Certificate
active
06211147
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment of ischemic wounds, for example, where the injury results from lack of oxygen due to poor circulation such as in the diseases diabetes, scleroderma, and the like, by the administration of relaxin. The present invention also relates to the promotion of angiogenesis.
BACKGROUND INFORMATION
Mature human relaxin is a hormonal peptide of approximately 6000 daltons known to be responsible for remodelling the reproductive tract before parturition, thus facilitating the birth process. This protein appears to modulate the restructuring of connective tissues in target organs to obtain the required changes in organ structure during pregnancy and parturition. See, Hisaw, F. L., Proc. Soc. Exp. Biol. Med., 23: 661-663 (1926); Schwabe, C., et al., Biochem. Biophys. Res. Comm., 75: 503-570 (1977); James, R. et al., Nature, 267: 544-546 (1977). A concise review of relaxin was provided by Sherwood, D. in
The Physiology of Reproduction,
Chapter 16, “Relaxin”, Knobil, E. and Neill, J., et al. (eds.), (Raven Press Ltd., New York), pp. 585-673 (1988). Circulating levels of relaxin are elevated for the entire nine months of pregnancy and drop quickly following delivery.
While predominantly a hormone of pregnancy, relaxin has also been detected in the non-pregnant female as well as in the male. Bryant-Greenwood, G. D., Endocrine Reviews, 3: 62-90 (1982) and Weiss, G., Ann. Rev. Physiol., 46:43-52 (1984).
Relaxin has been purified from a variety of species including porcine, murine, equine, shark, tiger, rat, dogfish and human, and shows at least primary and secondary structural homology to insulin and the insulin-like growth factor. In the human, relaxin is found in most abundance in the corpora lutea (CL) of pregnancy. However, specific nuclei in the brain have relaxin receptors and other nuclei contain messenger RNA for relaxin. Several nuclei with cells bearing relaxin receptors are found in the area of the hypothalamus.
Two human gene forms have been identified, (H1) and (H2). Hudson, P., et al., Nature, 301: 628-631 (1983); Hudson, P., et al., The EMBO Journal, 3: 2333-2339 (1984); and U.S. Pat. Nos. 4,758,516 and 4,871,670. Only one of the gene forms (H2) has been found to be transcribed in CL. It remains unclear whether the (H1) form is expressed at another tissue site, or whether it represents a pseudo-gene. When synthetic human relaxin (H2) and certain human relaxin analogs were tested for biological activity, the tests revealed a relaxin core necessary for biological activity as well as certain amino acid substitutions for methionine that did not affect biological activity. Johnston, et al., in
Peptides: Structure and Function, Proc. Ninth American Peptide Symposium,
Deber, C. M., et al. (eds.) (Pierce Chem. Co. 1985).
Methods of making relaxin are also described in U.S. Pat. No. 4,835,251 and in co-pending U.S. Ser. Nos. 07/908,766 (PCT US90/02085) and 08/080,354 (PCT US94/0699). Methods of using relaxin in cardiovascular therapy and in the treatment of neurodegenerative diseases are described in U.S. Pat. No. 5,166,191 and in U.S. Ser. No. 07/902,637 (PCT US92/06927). Certain formulations of human relaxin are described in allowed U.S. Ser. No. 08/050,745.
Recombinant human relaxin (H2) in currently in Phase I human clinical trials in scleroderma patients. Scleroderma is a disease involving an imbalance in tissue reformation giving rise to the overproduction of collagen, and ultimately resulting in swelling and hardening of the skin (and affected organs).
Vascular Endothelial Growth Factor (VEGF) has also been localized in situ in the corpus luteum (CL) of pregnancy, as well as the placenta and the endometrium. See Sharkey et al., J. Reprod. Fert. 99:609-615 (1993); Li et al. Growth Factors 22:277-282 (1994); Phillips et al. Endocrinology 127:965-967 (1990). VEGF, highly conserved glycoprotein secreted by macrophages, exhibits a potent ability to induce new vessel growth in vivo. VEGF is mitogen specific for endothelial cells and can induce both endothelial cell migration and serine and metalloproteinase expression (for review, see Thomas, K. A., J. Biol. Chem. 271:603-606 (1996). The strongest sites of VEGF expression are the fetal and maternal macrophages. Besides its proposed role in promoting new vessel growth during pregnancy, VEGF has also been proposed to be involved in persistent and dysregulated vessel growth in pathological conditions such as tumor metastasis, diabetic retinopathy, and rheumatoid arthritis.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a method of promoting angiogenesis in a mammal in need thereof by administering a therapeutically effective amount of relaxin. In a preferred embodiment, relaxin is administered in an amount sufficient to maintain a serum concentration of at least about 1 ng/ml. In a further preferred embodiment the relaxin is recombinant human relaxin (H2).
In another aspect, the invention relates to the treatment of infections or ischemic wounds by administering a therapeutically effective amount of relaxin. In a particularly preferred embodiment, the infection or ischemic wound is one where injury has resulted from lack of oxygen due to poor circulation.
In yet another aspect of the invention, there is provided a method of using relaxin for the manufacture of a medicant for the treatment of an infection or ischemic wound, or for the manufacture of a medicant for the promotion of angiogenesis. In preferred versions of these embodiments, the relaxin is recombinant human relaxin (H2).
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Parameters
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
The term “treatment” or “treating” means any therapeutic intervention in a mammal, including:
(i) prevention, that is, causing the clinical symptoms not to develop;
(ii) inhibition, that is, arresting the development of clinical symptoms; and/or
(iii) relief, that is, causing the regression of clinical symptoms.
The term “effective amount” means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected.
The term “relaxin” means human relaxin, including intact full length relaxin or a portion of the relaxin molecule that retains biological activity [as described in U.S. Pat. No. 5,023,321, preferably recombinant human relaxin (H2)] and other active agents with relaxin-like activity, such as Relaxin and portions that retain biological activity Like Factor (as described in U.S. Pat. No. 5,911,997 at SEQ ID NOS: 3 and 4, and column 5, line 27-column 6, line 4), relaxin analogs and portions that retain biological activity (as described in U.S. Pat. No. 5,811,395 at SEQ ID NOS: 1 and 2, and column 3, lines 16-40), and agents that competitevly displace bound relaxin from a receptor. Relaxin can be made by any method known to those skilled in the art, preferably as described in U.S. Pat. No. 4,835,251 and in co-pending U.S. Ser. Nos. 07/908,766 (PCT US90/02085) and 08/080,354 (PCT US94/0699).
The Role of Relaxin Promoting Angiogenesis
The invention is based, in part, on the surprising discovery that relaxin promotes angiogenesis in an in vivo assay, as described more fully below by way of working examples. Specifically, relaxin was found angiogenic in both a rabbit corneal injection protocol and by the matrigel subcutaneous insert vascularization protocol.
Also reported herein is the novel discovery that relaxin induces secretion of a potent angiogenic factor, Vascular Endothelial Growth Factor (“VEGF”), in the monocyte-like cell line THP-1. This finding furthe
Bozicevic Karl
Bozicevic, Field & Francis. LLP
Connetics Corporation
Kaufman Claire M.
Spector Lorraine
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