SELECTIVE AND POTENT INHIBITORY ANTIBODIES OF MYOSTATIN ACTIVATION

1 . An antibody or antigen-binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen binding fragment comprises six complementarity determining regions (CDRs), CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein CDRH1 comprises the sequence SYGMS (SEQ ID NO: 201), CDRH2 comprises the sequence SFTGSGGX 1 YYPDSVKG (SEQ ID NO: 202) wherein X 1 is T or A, CDRH3 comprises the sequence DLLIRFLEWSHYYGMDV (SEQ ID NO: 203), CDRL1 comprises the sequence RSSQSLLHSSGHNFLH (SEQ ID NO: 204), CDRL2 comprises the sequence EVSNRVS (SEQ ID NO: 205), and CDRL3 comprises the sequence X 1 QQTQYPX 2 T (SEQ ID NO: 206), wherein X 1 is M or Q, X 2 is P or G, wherein the CDR sequences are numbered according to the Kabat numbering system.

2 . The antibody or antigen-binding fragment thereof of claim 1 , comprising a CDRH1 comprising the sequence of SEQ ID NO: 201, a CDRH2 comprising any one of the sequences of SEQ ID NOs: 219 or 226, a CDRH3 comprising the sequence of SEQ ID NO: 220, a CDRL1 comprising the sequence of SEQ ID NO: 216, a CDRL2 comprising the sequence of SEQ ID NO: 222, and a CDRL3 comprising any one of the sequences of SEQ ID Nos: 223, 225, 227, or 298, as defined by the Kabat numbering system.

3 . The antibody or antigen-binding fragment thereof of claim 1 or claim 2 , comprising a CDRH1 comprising the sequence of SEQ ID NO: 201, a CDRH2 comprising the sequence of SEQ ID NO: 219, a CDRH3 comprising the sequence of SEQ ID NO: 220, a CDRL1 comprising the sequence of SEQ ID NO: 216, a CDRL2 comprising the sequence of SEQ ID NO: 222, and a CDRL3 comprising the sequence of SEQ ID NO: 223, as defined by the Kabat numbering system.

4 . The antibody or antigen-binding fragment thereof of claim 1 or claim 2 , comprising a CDRH1 comprising the sequence of SEQ ID NO: 201, a CDRH2 comprising the sequence of SEQ ID NO: 219, a CDRH3 comprising the sequence of SEQ ID NO: 220, a CDRL1 comprising the sequence of SEQ ID NO: 216, a CDRL2 comprising the sequence of SEQ ID NO: 222, and a CDRL3 comprising the sequence of SEQ ID NO: 225, as defined by the Kabat numbering system.

5 . The antibody or antigen-binding fragment thereof of claim 1 or claim 2 , comprising a CDRH1 comprising the sequence of SEQ ID NO: 201, a CDRH2 comprising the sequence of SEQ ID NO: 226, a CDRH3 comprising the sequence of SEQ ID NO: 220, a CDRL1 comprising the sequence of SEQ ID NO: 216, a CDRL2 comprising the sequence of SEQ ID NO: 222, and a CDRL3 comprising the sequence of SEQ ID NO: 227, as defined by the Kabat numbering system.

6 . The antibody or antigen-binding fragment thereof of claim 1 or claim 2 , comprising a CDRH1 comprising the sequence of SEQ ID NO: 201, a CDRH2 comprising the sequence of SEQ ID NO: 226, a CDRH3 comprising the sequence of SEQ ID NO: 220, a CDRL1 comprising the sequence of SEQ ID NO: 216, a CDRL2 comprising the sequence of SEQ ID NO: 222, and a CDRL3 comprising the sequence of SEQ ID NO: 298, as defined by the Kabat numbering system.

7 . The antibody or antigen binding fragment thereof of claim 1 or claim 2 , comprising a heavy chain variable domain sequence that is at least 90% identical to any one of SEQ ID NOs: 402, 409, or 420, and/or a light chain variable domain sequence that is at least 90% identical to any one of SEQ ID NOs: 412, 419, 421, or 422.

8 . The antibody or antigen binding fragment of claim 7 , comprising a pair of variable domain sequences comprising SEQ ID NOs: 402 and 412, SEQ ID NOs: 409 and 419, SEQ ID NOs: 420 and 421, or SEQ ID NOs: 420 and 422.

9 . The antibody or antigen binding fragment thereof of claim 1 or claim 2 , comprising a heavy chain sequence that is at least 70% identical to any one of SEQ ID NOs: 503, 507, or 509, and/or a light chain sequence that is at least 70% identical to any one of SEQ ID NOs: 504, 508, 510, or 511.

10 . The antibody or antigen binding fragment thereof of claim 9 , comprising a pair of heavy chain and light chain sequences comprising SEQ ID NOs: 503 and 504; SEQ ID NOs: 507 and 508; SEQ ID NOs: 509 and 510; or SEQ ID NOs: 509 and 511.

11 . An antibody or antigen binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen binding fragment comprises six complementarity determining regions (CDRs), CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein CDRH1 comprises the sequence SYGMS (SEQ ID NO: 201), CDRH2 comprises the sequence SITGSGGETYYPDSVKG (SEQ ID NO: 207), CDRH3 comprises the sequence DLLVRFLEWSHYYGMDV (SEQ ID NO: 208), CDRL1 comprises the sequence RSSQSLLHSSGHNFLH (SEQ ID NO: 204), CDRL2 comprises the sequence EVSNRVS (SEQ ID NO: 205), and CDRL3 comprises the sequence XIQATQFPRP (SEQ ID NO: 210), wherein X 1 is M or Q, wherein the CDR sequences are numbered according to Kabat.

12 . The antibody or antigen binding fragment thereof of claim 11 , wherein the CDRH1 comprises SEQ ID NO: 201, the CDRH2 comprises SEQ ID NO: 214, the CDRH3 comprises SEQ ID NO: 215, the CDRL1 comprises SEQ ID NO: 216, the CDRL2 comprises SEQ ID NO: 217, and the CDRL3 comprises SEQ ID NO: 218 or 224, as defined by the Kabat numbering system.

13 . The antibody or antigen binding fragment thereof of claim 11 or claim 12 , wherein the CDRH1 comprises SEQ ID NO: 201, the CDRH2 comprises SEQ ID NO: 214, the CDRH3 comprises SEQ ID NO: 215, the CDRL1 comprises SEQ ID NO: 216, the CDRL2 comprises SEQ ID NO: 217, and the CDRL3 comprises SEQ ID NO: 218, as defined by the Kabat numbering system.

14 . The antibody or antigen binding fragment thereof of claim 11 or claim 12 , wherein the CDRH1 comprises SEQ ID NO: 201, the CDRH2 comprises SEQ ID NO: 214, the CDRH3 comprises SEQ ID No: 215, the CDRL1 comprises SEQ ID NO: 216, the CDRL2 comprises SEQ ID NO: 217, and the CDRL3 comprises SEQ ID NO: 224, as defined by the Kabat numbering system.

15 . The antibody or antigen binding fragment thereof of claim 11 or claim 12 , comprising a heavy chain variable domain sequence that is at least 90% identical to any one of SEQ ID NOs: 400 or 407, and/or a light chain variable domain sequence that is at least 90% identical to any one of SEQ ID NOs: 410 or 417.

16 . The antibody or antigen binding fragment of claim 7 , comprising a pair of variable domain sequences comprising SEQ ID NOs: 400 and 410, or SEQ ID NOs: 407 and 417.

17 . The antibody or antigen binding fragment thereof of claim 11 or claim 12 , comprising a heavy chain sequence that is at least 70% identical to any one of SEQ ID NOs: 501 or 505, and/or a light chain sequence that is at least 70% identical to any one of SEQ ID NOs: 502 or 506.

18 . The antibody or antigen binding fragment thereof of claim 9 , comprising a pair of heavy chain and light chain sequences comprising SEQ ID NOs: 501 and 502 or SEQ ID NOs: 505 and 506.

19 . An antibody or antigen binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen binding fragment comprises six complementarity determining regions (CDRs), CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:

CDRH1 comprises the sequence GFTFSSYG (SEQ ID NO: 3);

CDRH2 comprises the sequence FTGSGGX 1 (SEQ ID NO: 291) wherein X 1 is selected from T and A;

CDRH3 comprises the sequence ARDLLIRFLEWSHYYGMDV (SEQ ID NO: 257);

CDRL1 comprises the sequence QSLLHSSGHNF (SEQ ID NO: 258);

CDRL2 comprises the sequence EVSNRVS (SEQ ID NO: 289); and

CDRL3 comprises the sequence X 1 QQTQYPX 2 T (SEQ ID NO: 292), wherein X 1 is M or Q and X 2 is selected from P and G, wherein the CDR sequences are numbered according to IMGT.

20 . The antibody or antigen binding fragment of claim 19 , comprising a heavy chain variable domain sequence selected from the amino acid sequences of SEQ ID NOs: 402 or 420.

21 . The antibody or antigen binding fragment of claim 19 or claim 20 , comprising a light chain variable domain sequence selected from the amino acid sequences of SEQ ID NOs: 412, 421, or 422.

22 . The antibody or antigen binding fragment of any one of claims 19-21 , comprising a pair of heavy chain and light chain variable domain sequences comprising the amino acid sequences of SEQ ID NOs: 402 and 412.

23 . The antibody or antigen binding fragment of any one of claims 19-21 , comprising a pair of heavy chain and light chain variable domain sequences comprising the amino acid sequences of SEQ ID NOs: 420 and 421.

24 . The antibody or antigen binding fragment of any one of claims 19-21 , comprising a pair of heavy chain and light chain variable domain sequences comprising the amino acid sequences of SEQ ID NOs: 420 and 422.

25 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment has an equilibrium dissociation constant, KD, of less than 5 nM, wherein, optionally, the antibody or antigen binding fragment has a KD of less than 1 nM (e.g. less than 0.7 nM, less than 0.5 nM, or less than 0.2 nM).

26 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment is capable of inhibiting mTLL-2-induced activation of myostatin with an IC50 of less than 1 nM as measured by functional ELISA.

27 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment has a 2:1 Fab:promyostatin binding stoichiometry, e.g., when the antibody and the antigen are mixed at 15 μM each and are allowed to form immune complexes at a neutral pH, and wherein the binding stoichiometry is measured by analytical size exclusion chromatography (SEC).

28 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment has at least 9-fold, e.g., at least 10-fold, greater pH sensitive binding as compared to an antibody having a heavy chain variable domain sequence of Ab2 and a light chain variable domain sequence of Ab2.

29 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment is capable of reducing total serum myostatin levels as compared to a background level.

30 . The antibody or antigen binding fragment thereof of any one of the preceding claims , wherein the antibody or antigen binding fragment cross-competes for binding to pro/latent myostatin with an antibody having a heavy chain variable domain sequence of Ab2 and a light chain variable domain sequence of Ab2.

31 . An antibody or antigen-binding fragment thereof that specifically binds to pro/latent myostatin, wherein the antibody or antigen binding fragment comprises six complementarity determining regions (CDRs), CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein:

CDRH1 comprises the amino acid sequence SYGMS (SEQ ID NO: 201);

CDRH2 comprises the amino acid sequence SFTGSGGTYYPDSVKG (SEQ ID NO: 219);

CDRH3 comprises the amino acid sequence DLLIRFLEWSHYYGMDV (SEQ ID NO: 220);

CDRL1 comprises the amino acid sequence RSSQSLLHSSGHNFLH (SEQ ID NO: 216);

CDRL2 comprises the amino acid sequence EVSNRVS (SEQ ID NO: 222); and

CDRL3 comprises the amino acid sequence MQQTQYPPT (SEQ ID NO: 223), wherein the CDR sequences are numbered according to Kabat.

32 . The antibody or antigen-binding fragment of claim 31 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 402 or a sequence that is at least 95% identical thereto, and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 412 or a sequence that is at least 95% identical thereto.

33 . The antibody or antigen-binding fragment of claim 31 or 32 , comprising a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 503 or a sequence that is at least 95% identical thereto; and/or a light chain sequence comprising the amino acid sequence of SEQ ID NO: 504 or a sequence that is at least 95% identical thereto.

34 . The antibody or antigen-binding fragment of any one of claims 31-33 , comprising the amino acid sequence of SEQ ID NO: 503 and the amino acid sequence of SEQ ID NO: 504.

35 . An antibody or antigen-binding fragment thereof that competes for binding to a prodomain of human pro/latent myostatin with Ab2 or binds to a region of the prodomain of human pro/latent myostatin at an epitope that comprises one or more amino acid residues of the sequence FVQILRLIKPMKDGTRYTGIRSLK (SEQ ID NO: 57) (amino acid positions 147-170 of human proMyostatin, as numbered according to SEQ ID NO: 52) and/or one or more amino acid residues of the sequence KALDEN (SEQ ID NO: 118) (amino acid positions 205-210 of human proMyostatin, as numbered according to SEQ ID NO: 52), wherein the antibody or antigen-binding fragment is not Ab2;

wherein the antibody binds the antigen in a pH-dependent manner as measured by a BLI-based in vitro binding assay (e.g., Octet®); and/or

wherein the antibody is capable of inhibiting myostatin activation with an IC50 of less than 1 nM (e.g., less than 0.5 nM), as measured by functional ELISA, e.g., comprising detection of the presence of mature myostatin in an assay mixture comprising an antibody-antigen immune complex and mTLL-2.

36 . The antibody or antigen-binding fragment thereof of claim 35 , wherein i) the L-CDR1 of the antibody shares no more than 20% sequence identity with the L-CDR1 of Ab2; ii) the L-CDR2 of the antibody shares no more than 30% sequence identity with the L-CDR2 of Ab2; and/or, iii) the L-CDR3 of the antibody shares no more than 10% of sequence identity with the L-CDR3 of Ab2, or wherein the heavy chain and light chain variable domains of the antibody share a cumulative sequence identity of less than 70% with the heavy chain variable region and light chain variable region sequences of Ab2.

37 . The antibody or antigen-binding fragment thereof of claim 35 or claim 36 , wherein the antibody dissociates from bound antigen at a higher rate in an acidic condition than in a neutral condition.

38 . The antibody or antigen-binding fragment thereof of any one of claims 35-37 , wherein the antibody or antigen-binding fragment binds pro/latent myostatin with a bivalent KD of less than 1 nM (e.g. less than 0.7 nM, less than 0.5 nM, or less than 0.2 nM) as measured by an SPR-based in vitro binding assay (e.g., Bicore™).

39 . The antibody or the antigen-binding fragment according to any one of claims 35-38 , wherein the antibody is capable of binding to the antigen with a 1:2 antibody-to-antigen stoichiometry, when the antibody and the antigen are mixed at 15 μM each and are allowed to form immune complexes at a neutral pH, and wherein the binding stoichiometry is measured by analytical size exclusion chromatography (SEC).

40 . The antibody or the antigen-binding fragment according to any one of claims 35-39 , comprising the antibody or antigen binding fragment of any one of claims 1-24 .

41 . The antibody or the antigen-binding fragment according to any one of claims 1-40 , wherein the antigen-binding fragment is incorporated into an engineered construct comprising:

a first monovalent arm capable of selectively binding human latent myostatin, and inhibiting myostatin activation; and

a second monovalent arm that binds a second target;

wherein, optionally, the engineered construct is a bispecific antibody.

42 . An antibody or antigen-binding fragment thereof that binds to the prodomain of human pro/latent myostatin, wherein the antibody or antigen-binding fragment:

(a) binds pro/latent myostatin with a bivalent KD of less than 1 nM (e.g. less than 0.7 nM, less than 0.5 nM, or less than 0.2 nM) as measured by an SPR-based in vitro binding assay (e.g., Biacore™).

(b) is capable of inhibiting myostatin activation with an IC50 of less than 1 nM (e.g., less than 0.7 nM), as measured by functional ELISA, e.g., wherein the measurement comprises detection of the presence of mature myostatin in an assay mixture comprising an antibody-antigen immune complex and mTLL-2;

(c) dissociates from bound antigen at a higher rate in an acidic condition than in a neutral condition as measured by a BLI-based in vitro binding assay (e.g., Octet®); and

(d) is capable of binding to the antigen with a 1:2 antibody-to-antigen stoichiometry, e.g., when the antibody and the antigen are mixed at 15 μM each and are allowed to form immune complexes at a neutral pH, and wherein the binding stoichiometry is measured by analytical size exclusion chromatography (SEC).

43 . An antibody or antigen-binding fragment thereof that binds to the prodomain of human pro/latent myostatin, wherein the antibody or antigen-binding fragment:

(a) binds pro/latent myostatin with a bivalent KD of less than 1 nM (e.g. less than 0.7 nM, less than 0.5 nM, or less than 0.2 nM)

(b) inhibits myostatin activation

(c) dissociates from bound antigen at a higher rate in an acidic condition than in a neutral condition; and

(d) is capable of binding to the antigen with a 1:2 antibody-to-antigen stoichiometry, when the antibody and the antigen are mixed at higher concentrations (e.g. 5 μM each, 10 μM each, 15 μM each, or higher) and are allowed to form immune complexes at a neutral pH, and wherein the binding stoichiometry is measured by analytical size exclusion chromatography (SEC) and

(e) is capable of binding to the antigen with a 1:1 antibody-to-antigen stoichiometry, when the antibody:

antigen complex is present at lower concentrations (e.g., at 0.45 μM or lower).

44 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of the preceding claims and a pharmaceutically acceptable excipient, wherein, optionally, the composition further comprises a second agent, e.g., a GLP-1 pathway activator (e.g., a GLP-1R agonist or GLP-1 analog) and/or a biguanide (e.g., metformin).

45 . The antibody or antigen-binding fragment of any one of claims 1-43 , or the pharmaceutical composition of claim 44 , for use in the treatment or prevention of one or more of the following conditions in a human subject:

muscle disorders (e.g., muscle atrophies or myopathies), metabolic disorders (e.g., obesity or diabetes), bone disorders (e.g., bone loss), cardiovascular diseases (e.g., heart failure), and chronic inflammation and inflammatory diseases (e.g., chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF), or rheumatoid arthritis (RA)), or a liver disease (e.g., fatty liver disease, NAFLD, or NASH);

wherein the treatment comprises administering the antibody, antigen-binding fragment, or pharmaceutical composition in an effective amount to treat or prevent the one or more of conditions.

46 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises a metabolic disorder, wherein, optionally, the metabolic disorder comprises diabetes and/or obesity.

47 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 46 , wherein the obesity is pediatric obesity, optionally wherein the antibody or antigen-binding fragment comprises Ab109 or an antigen binding fragment thereof.

48 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the antibody or antigen-binding fragment is administered in conjunction with a second agent suitable for treating diabetes or obesity.

49 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises a metabolic disorder associated with impaired neurological signaling, wherein, optionally, the metabolic disorder is associated with a muscle disorder, wherein optionally the muscle disorder is spinal cord injury, muscular dystrophy, or muscular atrophy.

50 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 49 , wherein the condition associated with impaired neurological signaling is a neuromuscular disorder.

51 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises a liver disease, wherein optionally the liver disease comprises fatty liver disease, NAFLD, or NASH, wherein, optionally, the subject is not treated with a TGFβ inhibitor (e.g., TGFβ1 inhibitor).

52 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises a bone disorder, wherein optionally the bone disorder comprises bone loss.

53 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises a cardiovascular disease, wherein optionally the cardiovascular disease comprises heart failure.

54 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 45 , wherein the one or more conditions comprises chronic inflammation or an inflammatory disease, wherein optionally the chronic inflammation or inflammatory disease comprises CKD, IPF, or RA.

55 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-54 , wherein the pharmaceutical composition, antibody, or antigen-binding fragment is administered in conjunction with a GLP-1 pathway activator, wherein, optionally, the subject is on a diet and/or exercise regimen.

56 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 55 , wherein the GLP-1 pathway activator is semaglutide, liraglutide, tirzepatide, or retatrutide.

57 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 55 or claim 56 , wherein the GLP-1 pathway activator is administered at a lower dose than the dose approved for use of the GLP-1 pathway activator as a monotherapy.

58 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 57 , wherein the second agent is a biguanide (e.g., metformin).

59 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-58 , wherein the treatment comprises administering an effective amount of the antibody, the antigen binding fragment thereof, or the pharmaceutical composition sufficient to slow fat accumulation in the subject by at least 10% as compared to the rate of fat accumulation in the subject before receiving the treatment.

60 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-59 , wherein the treatment comprises administering an effective amount of the antibody, the antigen binding fragment thereof, or the pharmaceutical composition sufficient to reduce fat mass in the subject by at least 5% (e.g., at least 10%, 15%, 20%, 25%, or more) as compared to baseline.

61 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-60 , wherein the treatment comprises administering an effective amount of the antibody, the antigen binding fragment thereof, or the pharmaceutical composition sufficient to reduce visceral fat mass by at least 5% as compared to baseline.

62 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 46-61 , wherein the treatment comprises administering an effective amount of the antibody, the antigen binding fragment thereof, or the pharmaceutical composition sufficient to reduce subcutaneous fat mass by at least 5% as compared to baseline.

63 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-62 , wherein the treatment comprises administering an effective amount of the antibody, the antigen binding fragment thereof, or the pharmaceutical composition sufficient to prevent loss of lean mass in the subject.

64 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to any one of claims 45-63 , wherein the pharmaceutical composition, antibody, or antigen-binding fragment is formulated for subcutaneous administration.

65 . The antibody or antigen-binding fragment thereof or pharmaceutical composition for use according to claim 61 , wherein the subcutaneous formulation comprises about 100-200 mg/mL of the antibody or antigen-binding fragment.

66 . The antibody or antigen-binding fragment thereof according to any one of claims 1-43 , or the pharmaceutical composition according to claim 44 and a second agent suitable for treating a metabolic disorder (e.g., a GLP-1 pathway activator and/or a biguanide such as metformin) for use in the treatment of a metabolic disorder in a subject, wherein the treatment comprises administration of the antibody or the antigen-binding fragment, or the pharmaceutical composition and the second agent in amounts effective to treat the metabolic disorder, wherein, optionally the metabolic disorder is obesity, diabetes, or both, wherein, further optionally, the effective amount of the second agent is below the recommended monotherapy dose for the second agent.

67 . The antibody, antigen-binding fragment thereof, or the pharmaceutical composition, and the second agent for use according to claim 66 , wherein the use comprises subcutaneous administration.

68 . The antibody, antigen-binding fragment or the pharmaceutical composition, and the second agent for use according to claim 66 or claim 67 , wherein the metabolic disorder comprises: adrenoleukodystrophy, diabetes type 1, diabetes type 2, Gaucher disease, glucose galactose malabsorption, hereditary hemochromatosis, Lesch-Nyhan syndrome, maple syrup urine disease, Menkes syndrome, NAFLD, NASH, Niemann-Pick disease, obesity, pancreatic cancer, phenylketonuria, Pompe disease (Glycogen storage disease type II), Prader-Willi syndrome, porphyria, Refsum disease, Tangier disease, Tay-Sachs disease, Wilson's disease, or Zellweger syndrome.

69 . A biguanide for use in treating obesity or in improving body composition in a subject, wherein the treatment comprises administration of the biguanide to the subject in conjunction with an agent that is not a GLP-1 receptor agonist, wherein, optionally, the agent comprises a myostatin inhibitor.

70 . The biguanide for use according to claim 69 , wherein the myostatin inhibitor is a non-selective myostatin inhibitor or a selective myostatin inhibitor, optionally wherein the myostatin inhibitor comprises the antibody, antigen-binding fragment thereof, according to any one of claims 1-43 .

71 . The biguanide for use according to claim 69 or claim 70 , wherein the biguanide is metformin.

72 . A myostatin inhibitor for use in treating obesity or in improving body composition in a subject, wherein the treatment comprises administration of the myostatin inhibitor to the subject in conjunction with a biguanide, and wherein the subject is not on a GLP-1 receptor agonist therapy at the time of the administration, and wherein the subject is overweight or obese but is not diabetic, wherein, optionally, the biguanide is metformin.

73 . A biguanide and a myostatin inhibitor for use in treating obesity or in improving body composition in a subject, wherein the treatment comprises administration of the biguanide and the myostatin inhibitor to the subject, wherein the subject is not on a GLP-1 receptor agonist therapy at the time of the administration;

wherein, optionally, the biguanide is metformin;

wherein, further optionally, the subject is overweight or obese but is not diabetic.

74 . A myostatin-selective inhibitor and metformin for use in treating obesity or in improving body composition in a subject, comprising administration of a myostatin-selective inhibitor and metformin to the subject, wherein, optionally, the subject is not on a GLP-1 receptor agonist therapy at the time of the administration.

75 . The myostatin inhibitor, myostatin-selective inhibitor, biguanide (e.g., metformin) or the combination for use according to any one of claims 69-74 , wherein the subject:

i) has low tolerance to GLP-1 receptor agonists;

ii) is a woman of child-bearing potential;

iii) is diagnosed with cancer or is at risk of developing cancer; and/or

iv) is at risk of suicidal ideation, self-harm or depression.

76 . The myostatin inhibitor or myostatin-selective inhibitor, biguanide (e.g., metformin), or the combination for use according to any one of claims 69-75 , wherein the myostatin inhibitor is:

i) an antibody that binds latent myostatin, and inhibits activation of myostatin; or,

ii) a neutralizing antibody that binds mature myostatin but does not bind Activin A or GDF11, wherein optionally the neutralizing antibody is trevogrumab or a variant thereof,

wherein, optionally, the myostatin inhibitor does not cause a reduction in bone mineral density as compared to baseline, as measured by dual-energy x-ray absorptiometry.

77 . The myostatin inhibitor, myostatin-selective inhibitor, biguanide (e.g., metformin), or the combination for use according to any one of claims 69-76 , wherein the myostatin inhibitor is selected from: an antibody or antigen binding fragment thereof according to any one of claims 1-43 ; apitegromab; and GYM329.

78 . Metformin and a non-selective myostatin inhibitor for use in treating obesity or in improving body composition in a subject, comprising administration of metformin and the non-selective myostatin inhibitor to the subject,

wherein the subject is not on a GLP-1 receptor agonist therapy at the time of the administration;

wherein optionally the subject is not a woman of child-bearing potential;

wherein, further, optionally the non-selective myostatin inhibitor is selected from:

i) an antibody that binds ActRIIB or ActRIIA;

ii) a neutralizing antibody that binds myostatin and at least one additional structurally related ligand selected from GDF11 and Activin A; and

iii) a ligand trap capable of binding mature myostatin.

79 . The metformin and non-selective myostatin inhibitor for use according to claim 74 , wherein the body composition is measured by fat mass to lean mass ratio before and after the administration.

80 . The antibody or antigen binding fragment thereof, pharmaceutical composition, or use according to any one of the preceding claims , wherein the myostatin-selective inhibitor does not cause a reduction in bone mineral density as compared to baseline, as measured by dual-energy x-ray absorptiometry.

81 . A method of treating a subject for obesity or improving body composition, comprising administering a myostatin-selective inhibitor to a subject who has discontinued treatment with a GLP-1 receptor agonist.

82 . The method of claim 81 , wherein the subject was administered the GLP-1 receptor agonist for at least 12 weeks (e.g., at least 6 months).

83 . The method of claim 81 or claim 82 , wherein the GLP-1 receptor agonist comprises semaglutide or tirzepatide.

84 . The method of any one of claims 81-83 , wherein administering the myostatin-selective inhibitor reduces fat mass by at least 10% relative to a subject not administered the myostatin-selective inhibitor after discontinuing the GLP-1 receptor agonist.

85 . The method of any one of claims 81-84 , wherein administering the myostatin-selective inhibitor prevents regain of fat mass by more than 20% as compared to a subject after discontinuing the GLP-1 receptor agonist but is not administered a myostatin-selective inhibitor, wherein the myostatin-selective inhibitor prevents the regain of fat mass for up to 6 months from the time of discontinuing the GLP-1 receptor agonist.

86 . The method of any one of claims 81-85 , wherein administering the myostatin-selective inhibitor prevents a decrease in the ratio of lean mass to fat mass by more than 20% as compared to a subject after discontinuing the GLP-1 receptor agonist but is not administered a myostatin-selective inhibitor, wherein the myostatin-selective inhibitor prevents the regain of fat mass for up to 6 months from the time of discontinuing the GLP-1 receptor agonist.

87 . The method of any one of claims 81-86 , wherein the subject is further administered metformin.

88 . The method of any one of claims 81-87 , wherein the myostatin selective inhibitor comprises an antibody or antigen-binding fragment according to any one of claims 1-3 .

89 . A method of reducing fat mass regain in a subject after discontinuing treatment with a GLP-1 receptor agonist, wherein the method comprises administering to the subject a myostatin-selective inhibitor (e.g., any one of the myostatin-selective antibodies or the antigen-binding fragments according to any one of claims 1-43 ) in an amount effective to reduce fat mass gain as compared to a subject who has discontinued treatment with a GLP-1 receptor agonist but is not treated with the myostatin-selective inhibitor.

90 . The method of claim 89 , wherein the administration reduces fat mass regain as compared to a subject after discontinuing the GLP-1 receptor agonist but is not administered a myostatin-selective inhibitor, wherein the myostatin-selective inhibitor prevents the regain of fat mass for up to 6 months from the time of discontinuing the GLP-1 receptor agonist.

91 . The method of claim 89 or claim 90 , wherein the administration reduces fat mass regain by at least 10% (e.g., at least 10%, 20%, 25%, or more) as compared to a subject after discontinuing the GLP-1 receptor agonist but is not administered a myostatin-selective inhibitor.

92 . The method of any one of claims 89-91 , wherein the myostatin-selective inhibitor is administered prior to discontinuing the GLP-1 receptor agonist (e.g., in conjunction with the GLP-1 receptor agonist).

93 . The method of any one of claims 89-92 , wherein the myostatin-selective inhibitor is administered within 6 months of discontinuing the GLP-1 receptor agonist.

94 . The method of any one of claims 89-93 , wherein the myostatin selective inhibitor comprises an antibody or antigen-binding fragment according to any one of claims 1-43 .

95 . A method of reducing liver fat mass in a subject, e.g., in an obese subject and/or a subject with fatty liver disease, comprising administering to the subject a myostatin-selective inhibitor in an amount effective to reduce liver fat mass, preferably in a subject receiving a GLP-1 agonist and/or metformin.

96 . The method of claim 95 , wherein administering the myostatin-selective inhibitor reduces liver fat mass by at least 10% (e.g., 10%, 20%, 25%, or more) relative to the subject's liver fat mass prior to administering the myostatin-selective inhibitor.

97 . A method of improving bone strength and/or preventing bone loss in a subject (e.g., an obese subject), comprising administering to the subject a myostatin-selective inhibitor in an amount effective to improve bone strength and/or prevent bone loss as compared to a subject (e.g., an obese subject) who has not been administered the myostatin-selective inhibitor.

98 . The method of claim 97 , wherein the administration of the myostatin-selective inhibitor reduces bone fracture by at least 10% (e.g., 10%, 20%, 25%, or more) as compared to a subject who has not been administered the myostatin-selective inhibitor.

99 . The method of any one of claims 95-98 , wherein the subject is receiving or has received a GLP-1 agonist and/or metformin, wherein, optionally, the GLP-1 agonist comprises semaglutide or tirzepatide.

100 . A method of improving blood glucose or hemoglobin A1C (A1C) levels in a pre-diabetic or diabetic subject who is receiving or has received a GLP-1 agonist, comprising administering to the subject a myostatin-selective inhibitor in an amount effective to reduce blood glucose or A1C levels as compared to levels before the administration of the myostatin-selective inhibitor.

101 . The method of claim 100 , wherein the administering of the myostatin-selective inhibitor reduces blood glucose or A1C levels by at least 10% (e.g., 10%, 20%, 25%, or more) relative to the subject's blood glucose or A1C levels prior to administering the myostatin-selective inhibitor, wherein, optionally, the reduction in glucose is a reduction in fasted glucose.

102 . The method of claim 100 or claim 101 , wherein the reduction in blood glucose or A1C levels is greater than a reduction in blood glucose or A1C levels achieved by administering a GLP-1 receptor agonist alone.

103 . The method of any one of claims 100-102 , wherein the GLP-1 agonist comprises semaglutide or tirzepatide.

104 . The method of any one of claims 100-103 , wherein the subject is receiving or has received metformin.

105 . The method of any one of claims 95-104 , wherein the myostatin selective inhibitor comprises an antibody or antigen-binding fragment according to any one of claims 1-43 .

106 . A myostatin-selective inhibitor for use in treating obesity or in improving body composition in a subject, wherein the treatment comprises administering to the subject the myostatin-selective inhibitor in conjunction with a GLP-1 receptor agonist and a biguanide, wherein the myostatin-selective inhibitor, the GLP-1 receptor agonist, and the biguanide, are administered in effective amounts to treat obesity or improve body composition.

107 . The myostatin-selective inhibitor for use of claim 106 , wherein the GLP-1 receptor agonist comprises semaglutide or tirzepatide.

108 . The myostatin-selective inhibitor for use of claim 106 or claim 107 , wherein the biguanide is metformin.

109 . The myostatin-selective inhibitor for use of any one of claims 106-108 , wherein the myostatin selective inhibitor comprises an antibody or antigen-binding fragment according to any one of claims 1-43 .

110 . A myostatin inhibitor for use in the treatment of chronic inflammation in a subject, wherein the treatment comprises administering to the subject an effective amount of the myostatin inhibitor to treat the chronic inflammation, wherein optionally the chronic inflammation is inflammation associated with a muscle disorder (e.g., Duchenne muscular dystrophy (DMD)), inflammation associated with chronic kidney disease (CKD), inflammation associated with nonalcoholic fatty liver disease (NAFLD), inflammation associated with nonalcoholic steatohepatitis (NASH), inflammation associated with idiopathic pulmonary fibrosis (IPF), inflammation associated with obesity, inflammation associated with pancreatitis, and/or inflammation associated with an autoimmune disease (e.g., rheumatoid arthritis (RA)).

111 . The myostatin inhibitor for use according to claim 110 , wherein the myostatin inhibitor is used in conjunction with an additional therapy, wherein optionally the additional therapy comprises a GLP-1 receptor agonist, a TGFβ1 inhibitor (e.g., a LTBP-selective TGFβ1 inhibitor), and/or an iron-enhancing agent (e.g., a HIF-PH inhibitor or an RGMc inhibitor).

112 . The myostatin inhibitor for use according to claim 110 or claim 111 , wherein the myostatin inhibitor is a myostatin-selective inhibitor, wherein optionally the myostatin-selective inhibitor is an antibody or antigen-binding fragment of any one of claims 1-40 , wherein, further optionally, the myostatin-selective inhibitor is Ab109, Ab133, Ab141, apitegromab, trevogrumab, GYM329, or any variant thereof.

113 . The myostatin inhibitor for use according to claim 110 or claim 111 , wherein the myostatin inhibitor is a non-selective inhibitor of myostatin, wherein optionally the non-selective inhibitor of myostatin is an anti-myostatin-Adnectin, an ActRII receptor antagonist (e.g., bimagrumab or variant thereof), a follistatin-based agent (e.g., an AAV-follistatin or a follistatin-based ligand trap), a soluble ActRII-based ligand trap, or an anti-myostatin neutralizing antibody.