Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-07
2002-01-22
Romeo, David (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S350000, C424S198100
Reexamination Certificate
active
06340668
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates, inter alia, to a novel family of purified proteins designated BMP-11, DNA molecules encoding them, and processes for obtaining them. The inventors have previously designated the BMP-11 proteins as Activin WC. The BMP-11 proteins may be useful to induce bone and/or cartilage formation and in wound healing and tissue repair, or for augmenting the activity of other bone morphogenetic proteins. The BMP-11 proteins may also be useful to regulate the production of follicle stimulating hormone, for contraception, to promote neuronal cell survival, to stimulate hematopoiesis, and to suppress the development of gonadal tumors. U.S. Pat. No. 4,798,885 disclosed DNA encoding the prepro inhibin &agr; and &bgr; chains. U.S. Pat. No. 5,071,834 discloses pharmaceutical compositions of activin with two beta
B
chains formulated in a pharmaceutically acceptable carrier. U.S. Pat. No. 5,102,807 discloses a purified inhibin protein which suppresses production of FSH without suppressing production of luteinizing hormone.
In addition, the BMP-11 proteins of the present invention are useful to modulate all aspects of neuronal cell development, particularly neuronal formation, growth, differentiation, proliferation, and especially neuronal maintenance.
SUMMARY OF THE INVENTION
BMP-11 protein is a member of the TGF-&bgr; superfamily of proteins. The TGF-&bgr; superfamily includes the family of proteins known as bone morphogenetic proteins (BMPs), as well as a group of proteins that are termed inhibin-&bgr;. As discussed further herein, when dimerized with another BMP-11 (homodimer), BMP-11 protein is expected to demonstrate BMP-11 activity, as further described herein, as may be measured in accordance with the assays described in the examples herein. When dimerized as a heterodimer with inhibin-&agr; proteins or with other inhibin-&bgr; proteins, the inhibin-&bgr;/BMP-11 heterodimer is expected to demonstrate effects on the production of follicle stimulating hormone (FSH), as described further herein. It is further expected that, in homodimeric form or in heterodimeric form with another member of the bone morphogenetic protein family, BMP-11 will exhibit BMP activity, i.e., the ability to induce the formation of bone, cartilage and/or other connective tissue. Thus, depending upon the environment of BMP-11, it may form dimers which will demonstrate either activin or inhibin activity, or bone, cartilage and/or other connective tissue-inducing activity. Accordingly, BMP-11 activity is defined as the ability to regulate the production of FSH in the assay described at Example 8 herein, or the ability to induce the formation of bone, cartilage and/or other connective tissue in the assays described at Examples 5 to 7 herein, as well as to modulate cell development, particularly neuronal formation, growth, differentiation, proliferation, and especially neuronal maintenance (Example 9).
Proteins termed inhibins and activins are produced in the gonad and exist naturally in follicular fluid. These proteins act at the level of the anterior pituitary gland to inhibit (inhibins) or stimulate (activins) the release of follicle-stimulating hormone (FSH) [for reviews see, e.g., Ying, S.-Y.,
Endocr. Rev.,
9:267-293 (1988) or Ling, N. et al,
Vitamins and Hormones,
44:1-46 (Academic Press 1988)]. Briefly, dimeric proteins comprised of one chain of inhibin &agr; and one chain of inhibin &bgr; (&bgr;
A
or &bgr;
B
) are termed inhibins and are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while other dimeric proteins comprised of two chains of inhibin &bgr; (&bgr;
A
or &bgr;
B
) are termed activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH) [see, e.g., Ling et al.,
Nature,
321:779-782 (1986) or Vale, et al.,
Nature,
321:776-779 (1986) or Mason et al.,
Nature,
318:659-663 (1985) or Forage et al.,
Proc. Natl. Acad. Sci. USA,
83:3091-3095 (1986)].
It is recognized that FSH stimulates the development of ova in mammalian ovaries (Ross et al., in Textbook of Endocrinology, ed. Williams, p. 355 (1981) and that excessive stimulation of the ovaries with FSH will lead to multiple ovulations. FSH is also important in testicular function. Thus, BMP-11, in heterodimers with a member of the inhibin &agr; family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility these mammals. BMP-11, as a homodimer or as a heterodimer with other protein subunits of the inhibin-&bgr; group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary. See, for example, U.S. Pat. No. 4,798,885. BMP-11 may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs. It is further contemplated that BMP-11 may be useful in promoting neuronal cell survival [see, e.g., Schubert et al.,
Nature,
344:868-870 (1990)], modulating hematopoiesis by inducing the differentiation of erythroid cells [see, e.g., Broxmeyer et al,
Proc. Natl. Acad. Sci. USA,
85:9052-9056 (1988) or Eto et al,
Biochem. Biophys. Res. Comm.,
142:1095-1103 (1987)], for suppressing the development of gonadal tumors [see, e.g., Matzuk et al.,
Nature,
360:313-319 (1992)] or for augmenting the activity of bone morphogenetic proteins [see, e.g., Ogawa et al.,
J. Biol. Chem.,
267:14233-14237 (1992)].
BMP-11 proteins may be further characterized by their ability to modulate the release of follicle stimulating hormone (FSH) in established in vitro bioassays using rat anterior pituitary cells as described [see, e.g., Vale et al,
Endocrinology,
91:562-572 (1972); Ling et al.,
Nature,
321:779-782 (1986) or Vale et al.,
Nature,
321:776-779 (1986)]. It is contemplated that the BMP-11 protein of the invention, when composed as a homodimer or a heterodimer with other inhibin &bgr; chains will exhibit stimulatory effects on the release of follicle stimulating hormone (FSH) from anterior pituitary cells as described [Ling et al.,
Nature,
321:779-782 (1986) or Vale et al.,
Nature,
321:776-779 (1986)]. Additionally, it is contemplated that the BMP-11 protein of the invention, when composed as a heterodimer with the inhibin a chain, will inhibit the release of follicle stimulating hormone (FSH) from anterior pituitary cells as described [see, e.g., Vale et al,
Endocrinology,
91:562-572 (1972). Therefore, depending on the particular composition, it is expected that the BMP-11 protein of the invention may have contrasting and opposite effects on the release of follicle stimulating hormone (FSH) from the anterior pituitary.
Activin A (the homodimeric composition of inhibin &bgr;
A
) has been shown to have erythropoietic-stimulating activity [see e.g. Eto et al.,
Biochem. Biophys. Res. Commun.,
142:1095-1103 (1987) and Murata et al.,
Proc. Natl. Acad. Sci. U.S.A.,
85:2434-2438 (1988) and Yu et al.,
Nature,
330:765-767 (1987)]. It is contemplated that the BMP-11 protein of the invention has a similar erythropoietic-stimulating activity. This activity of the BMP-11 protein may be further characterized by the ability of the BMP-11 protein to demonstrate erythropoietin activity in the biological assay performed using the human K-562 cell line as described by [Lozzio et al.,
Blood,
45:321-334 (1975) and U.S. Pat. No. 5,071,834].
The structures of several proteins, designated BMP-1 through BMP-9, have previously been elucidated. The unique inductive activities of these proteins, along with their presence in bone, suggests that they are important regulators of bone repair processes, and may be involved in the norma
Celeste Anthony J.
Thies R. Scott
Wozney John M.
Genetics Institute Inc.
Gyure Barbara
Kapinos Ellen J.
Romeo David
LandOfFree
Neuronal uses of BMP-11 does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Neuronal uses of BMP-11, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Neuronal uses of BMP-11 will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2845309