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Myostatin binding agents

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Title: Myostatin binding agents.
Abstract: The present invention provides binding agents comprising peptides capable of binding myostatin and inhibiting its activity. In one embodiment the binding agent comprises at least one myostatin-binding peptide attached directly or indirectly to at least one vehicle such as a polymer or an Fc domain. The binding agents of the present invention produced increased lean muscle mass when administered to animals and decreased fat to muscle ratios. Therapeutic compositions containing the binding agents of the present invention are useful for treating muscle-wasting disorders and metabolic disorders including diabetes and obesity. ...


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Inventors: HQ HAN, HOSUNG MIN, THOMAS CHARLES BOONE
USPTO Applicaton #: #20120083442 - Class: 514 48 (USPTO) - 04/05/12 - Class 514 


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The Patent Description & Claims data below is from USPTO Patent Application 20120083442, Myostatin binding agents.

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This application is a divisional of U.S. patent application Ser. No. 12/806,880, filed Aug. 23, 2010, which is a divisional of U.S. patent application Ser. No. 12/322,369, filed Jan. 30, 2009, now U.S. Pat. No. 7,803,923, which is a divisional of U.S. patent application Ser. No. 10/742,379, filed Dec. 19, 2003, now U.S. Pat. No. 7,511,012, which hereby claims benefit of U.S. provisional application Ser. No. 60/435,923, filed Dec. 20, 2002, the entire disclosure of each of the above applications is relied upon and incorporated by reference herein.

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled A-828-US-DIV3.txt created Oct. 20, 2011, which is 190 KB in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

Throughout this application various publications are referenced within parentheses or brackets. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.

FIELD OF THE INVENTION

The invention relates to growth factors and in particular to the growth factor myostatin and agents which bind myostatin and inhibit its activity.

BACKGROUND

Myostatin, also known as growth/differentiation factor 8 (GDF-8), is a transforming growth factor-β (TGF-β) family member known to be involved in regulation of skeletal muscle mass. Most members of the TGF-β-GDF family are expressed non-specifically in many tissue types and exert a variety of pleitrophic actions. However, myostatin is largely expressed in the cells of developing and adult skeletal muscle tissue and plays an essential role in negatively controlling skeletal muscle growth (McPherron et al. Nature (London) 387, 83-90 (1997)). Recent studies, however, indicate that low levels of myostatin expression can be measured in cardiac, adipose and pre-adipose tissues.

The myostatin protein has been highly conserved evolutionarily (McPherron et al. PNAS USA 94:12457-12461 (1997)). The biologically active C-terminal region of myostatin has 100 percent sequence identity between human, mouse, rat, cow, chicken, and turkey sequences. The function of myostatin also appears to be conserved across species as well. This is evident from the phenotypes of animals having a mutation in the myostatin gene. Two breeds of cattle, the Belgian Blue (Hanset R., Muscle Hypertrophy of Genetic Origin and its Use to Improve Beef Production, eds, King, J. W. G. & Menissier, F. (Nijhoff, The Hague, The Netherlands) pp. 437-449) and the Piedmontese (Masoero, G. & Poujardieu, B, Muscle Hypertrophy of Genetic Origin and its Use to Improve Beef Production., eds, King, J. W. G. & Menissier, F. (Nijhoff, The Hague, The Netherlands) pp. 450-459) are characterized by a “double muscling” phenotype and increase in muscle mass. These breeds were shown to contain mutations in the coding region of the myostatin gene (McPherron et al. (1997) supra). In addition, mice containing a targeted deletion of the gene encoding myostatin (Mstn) demonstrate a dramatic increase in muscle mass without a corresponding increase in fat. Individual muscles of Mstn−/− mice weigh approximately 100 to 200 percent more than those of control animals as a result of muscle fiber hypertrophy and hyperplasia (Zimmers et al. Science 296, 1486 (2002)).

Administration of myostatin to certain strains of mice has been shown to create a condition similar to muscle wasting disorders found associated with cancer, AIDS, and muscular dystrophy, for example. Myostatin administered as myostatin-producing CHO cells to athymic nude mice resulted in a wasting effect with a high degree of weight loss, a decrease of as much as 50% of skeletal muscle mass in addition to fat wasting, and severe hypoglycemia (Zimmers et al. supra).

Loss of myostatin appears to result in the retention of muscle mass and reduction in fat accumulation with aging. It has been shown that age-related increases in adipose tissue mass and decrease in muscle mass were proportional to myostatin levels, as determined by a comparison of fat and muscle mass in Mstn+/+ when compared with Mstn−/− adult knockout mice (McFerron et al. J. Clin. Invest 109, 595 (2002)). Mstn−/− mice showed decreased fat accumulation with age compared with Mstn+/+ mice.

In addition myostatin may play a role in maintaining blood glucose levels and may influence the development of diabetes in certain cases. It is known that, for example, skeletal muscle resistance to insulin-stimulated glucose uptake is the earliest known manifestation of non-insulin-dependent (type 2) diabetes mellitus (Corregan et al. Endocrinology 128:1682 (1991)). It has now been shown that the lack of myostatin partially attenuates the obese and diabetes phenotypes of two mouse models, the agouti lethal yellow (Ay) (Yen et al. FASEB J. 8:479 (1994)), and obese (Lepob/ob). Fat accumulation and total body weight of the Ay/a, Mstn−/− double mutant mouse was dramatically reduced compared with the Ay/a Mstn+/+ mouse (McFerron et al., (2002) supra). In addition, blood glucose levels in the Ay/a, Mstn−/− mice was dramatically lower than in Ay/a Mstn+/+ mice following exogenous glucose load, indicating that the lack of myostatin improved glucose metabolism. Similarly Lepob/ob Mstn−/− mice showed decreased fat accumulation when compared with the Lepob/ob Mstn+/+ phenotype.

Therefore, there is considerable evidence from the phenotypes of over-expressing and knockout animals that myostatin may play a role in contributing to a number of metabolic disorders including disorders resulting in muscle wasting, diabetes, obesity and hyperglycemia.

SUMMARY

OF THE INVENTION

The present invention is directed to binding agents which bind myostatin and inhibit its activity. The binding agents comprise at least one peptide capable of binding myostatin. The myostatin-binding peptides are preferably between about 5 and about 50 amino acids in length, more preferably between about 10 and 30 amino acids in length, and most preferably between about 10 and 25 amino acids in length. In one embodiment the myostatin-binding peptide comprises the amino acid sequence WMCPP (SEQ ID NO: 633). In another embodiment the myostatin binding peptides comprise the amino acid sequence Ca1a2Wa3WMCPP (SEQ ID NO: 352), wherein a1, a2 and a3 are selected from a neutral hydrophobic, neutral polar, or basic amino acid. In another embodiment the myostatin binding peptide comprises the sequence Cb1b2Wb3WMCPP (SEQ ID NO: 353), wherein b1 is selected from any one of the amino acids T, I, or R; b2 is selected from any one of R, S, Q; b3 is selected from any one of P, R and Q, and wherein the peptide is between 10 and 50 amino acids in length, and physiologically acceptable salts thereof. In another embodiment, the myostatin binding peptide comprises the formula:

c1c2c3c4c5c6Cc7c8Wc9WMCPPc10c11c12c13(SEQ ID NO: 354),

wherein:

c1 is absent or any amino acid;

c2 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

c3 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

c4 is absent or any amino acid;

c5 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

c6 is absent or a neutral hydrophobic, neutral polar, or basic amino acid;

c7 is a neutral hydrophobic, neutral polar, or basic amino acid;

c8 is a neutral hydrophobic, neutral polar, or basic amino acid;

c9 is a neutral hydrophobic, neutral polar or basic amino acid; and

c10 to c13 is any amino acid; and wherein the peptide is between 20 and 50 amino acids in length, and physiologically acceptable salts thereof.

A related embodiment the myostatin binding peptide comprises the formula:

d1d2d3d4d5d6Cd7d8Wd9WMCPPd10d11d12d13(SEQ ID NO: 355),

wherein

d1 is absent or any amino acid;

d2 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

d3 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

d4 is absent or any amino acid;

d5 is absent or a neutral hydrophobic, neutral polar, or acidic amino acid;

d6 is absent or a neutral hydrophobic, neutral polar, or basic amino acid;

d7 is selected from any one of the amino acids T, I, or R;

d8 is selected from any one of R, S, Q;

d9 is selected from any one of P, R and Q, and

d10 to d13 is selected from any amino acid,

and wherein the peptide is between 20 and 50 amino acids in length, and physiologically acceptable salts thereof.

Additional embodiments of binding agents comprise at least one of the following peptides:

(1) a peptide capable of binding myostatin, wherein the peptide comprises the sequence WYe1e2Ye3G, (SEQ ID NO: 356),

wherein e1 is P, S or Y,

e2 is C or Q, and

e3 is G or H, wherein the peptide is between 7 and 50 amino acids in length, and physiologically acceptable salts thereof;

(2) a peptide capable of binding myostatin, wherein the peptide comprises the sequence f1EMLf2SLf3f4LL, (SEQ ID NO: 455),

wherein f1 is M or I,

f2 is any amino acid,

f3 is L or F,

f4 is E, Q or D;

and wherein the peptide is between 7 and 50 amino acids in length, and physiologically acceptable salts thereof;

(3) a peptide capable of binding myostatin wherein the peptide comprises the sequence Lg1g2LLg3g4L, (SEQ ID NO: 456), wherein

g1 is Q, D or E,

g2 is S, Q, D or E,

g3 is any amino acid,

g4 is L, W, F, or Y, and wherein the peptide is between 8 and 50 amino acids in length, and physiologically acceptable salts thereof;

(4) a peptide capable of binding myostatin, wherein the peptide comprises the sequence h1h2h3h4h5h6h7h8h9 (SEQ ID NO: 457), wherein

h1 is R or D,

h2 is any amino acid,

h3 is A, T S or Q,

h4 is L or M,

h5 is L or S,

h6 is any amino acid,

h7 is F or E,

h8 is W, F or C,

h9 is L, F, M or K, and wherein the peptide is between 9 and 50 amino acids in length, and physiologically acceptable salts thereof.

In one embodiment, the binding agents of the present invention further comprise at least one vehicle such as a polymer or an Fc domain, and may further comprise at least one linker sequence. In this embodiment, the binding agents of the present invention are constructed so that at least one myostatin-binding peptide is attached to at least one vehicle. The peptide or peptides are attached directly or indirectly through a linker sequence, to the vehicle at the N-terminal, C-terminal or an amino acid sidechain of the peptide. In this embodiment, the binding agents of the present invention have the following generalized structure:

(X1)a—F1—(X2)b, or multimers thereof;

wherein F1 is a vehicle; and X1 and X2 are each independently selected from -(L1)c-P1; -(L1)c-P1-(L2)d-P2; -(L1)c-P1-(L2)d-P2-(L3)e-P3; and -(L1)c-P1-(L2)d-P2-(L3)e-P3-(L4)f-P4; wherein P1, P2, P3, and P4 are peptides capable of binding myostatin; and L1, L2, L3, and L4 are each linkers; and a, b, c, d, e, and f are each independently 0 or 1, provided that at least one of a and b is 1, and physiologically acceptable salts thereof.

In various embodiments of binding agents having this generalized structure, the peptides P1, P2, P3, and P4 can be independently selected from one or more of any of the peptides comprising the sequences provided above. P1, P2, P3, and P4 are independently selected from one or more peptides comprising any of the following sequences: SEQ ID NO: 633, SEQ ID NO: 352, SEQ ID NO: 353, SEQ ID NO: 354, SEQ ID NO: 355, SEQ ID NO: 356, SEQ ID NO: 455, SEQ ID NO: 456, or SEQ ID NO: 457.

In a further embodiment, the binding agents comprise peptides fused to an Fc domain, either directly or indirectly, thereby providing peptibodies. The peptibodies of the present invention display a high binding affinity for myostatin and can inhibit the activity of myostatin as demonstrated both in vitro using cell based assays and in animals.

The present invention also provides nucleic acid molecules comprising polynucleotides encoding the peptides, peptibodies, and peptide and peptibody variants and derivatives of the present invention.

The present invention provides pharmaceutically acceptable compositions comprising one or more binding agents of the present invention.

The binding agents of the present invention inhibit myostatin activity in vitro and in vivo. The binding agents of the present invention increase lean muscle mass in a treated animal and decreases fat mass as a percentage of body weight of the animal. The myostatin binding agents of the present invention increase muscular strength in treated animal models.

The present invention provides methods of inhibiting myostatin activity in animals including humans by administering an effective dosage of one or more binding agents to the subject. The present invention provides methods of increasing lean muscle mass in animals including humans by administering an effective dosage of one or more binding agents. The present invention further provides methods of treating myostatin-related disorders by administering a therapeutically effective dosage of one or more myostatin binding agents in a pharmaceutically acceptable composition to a subject. The present invention provides methods of treating muscle wasting disorders including muscular dystrophy, muscle wasting due to cancer, AIDS, rheumatoid arthritis, renal failure, uremia, chronic heart failure, age-related sarcopenia, prolonged bed-rest, spinal chord injury, stroke, bone fracture. The present invention also provides methods of treating metabolic disorders including obesity, diabetes, hyperglycemia, and bone loss.

The present invention also provides a method of increasing muscle mass in food animals by administering an effective dosage of one or more myostatin binding agents to the animal.

The present invention provides assays utilizing one or more myostatin binding agents to identify and quantitate myostatin in a sample. The assays may be diagnotic assays for measuring or monitoring myostatin levels in individuals with a myostatin related disorder or disease.



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stats Patent Info
Application #
US 20120083442 A1
Publish Date
04/05/2012
Document #
13310661
File Date
12/02/2011
USPTO Class
514/48
Other USPTO Classes
530300, 530328, 530329, 5303873, 514 216, 514 215, 514 214, 514 213, 536 231, 536 234, 4353201, 4352523, 4352542, 435348, 435419, 435325, 43525233, 435364, 435367, 435358, 435365, 435352, 435350, 435357, 435369, 435353, 435370, 435371, 435 691, 514 165, 514 164, 514 167, 514 166, 514 193, 514 154, 514/69, 436501, 435/721, 506/9
International Class
/
Drawings
6


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