Methods for inhibiting myostatin activation by administering anti-pro/latent myostatin antibodies

• US 10,287,345 B2
• Filed: 01/06/2017
• Issued: 05/14/2019
• Est. Priority Date: 01/08/2016
• Status: Active Grant

• Current Assignee: Scholar Rock, Inc. (Scholar Rock Holding Corp.)
• Original Assignee: Scholar Rock, Inc. (Scholar Rock Holding Corp.)
• Inventors: Donovan, Adriana, Straub, Michelle, Wawersik, Stefan
• Primary Examiner(s): Howard, Zachary C
• Application Number:
  US15/400,825
• Publication Number:
  US 20170198032A1
• Time in Patent Office: 858 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 21/06 Anabolic agents androgens A61P5/26
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 16/22 against growth factors ; against growth regulators
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/524 CH2 domain
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention relates to antibodies that specifically bind pro-myostatin and/or latent myostatin, and methods and uses thereof.

Claims

1. A method for inhibiting myostatin activation in a subject, the method comprising a step of:

administering to the subject a composition comprising an antibody, or antigen binding fragment thereof, that specifically binds pro-myostatin and latent myostatin and blocks release of mature myostatin, in an amount effective to cause two or more of the following in the subject;

(a) an increase in mass and/or function of a muscle tissue in the subject;

(b) a decrease in ratio of adipose-to-muscle tissue in the subject;

(c) a decrease in intramuscular fat infiltration in the subject; and

(d) prevention of muscle loss or atrophy in the subject;

wherein the subject is a human subject that benefits from reduced myostatin signaling;

wherein the amount is an amount that causes an increase in a level of circulating latent myostatin in a serum sample, as compared to a control; and

,

wherein the antibody, or antigen binding fragment thereof, comprises any one of the following;

i) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

24 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

30;

ii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO;

1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO;

4, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO;

10, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO;

12, a CDRL2 sequence that is at least 90% identical to SEQ ID NO;

18, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO;

22;

iii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

25 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

31;

iv) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

26 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

32;

v) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO;

1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO;

6, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO;

11, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO;

14, a CDRL2 sequence that is at least 90% identical to SEQ ID NO;

20, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO;

23;

vi) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

27 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

33;

vii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

28 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

34;

viii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to SEQ ID NO;

1, a CDRH2 sequence that is at least 90% identical to SEQ ID NO;

8, and a CDRH3 sequence that is at least 90% identical to SEQ ID NO;

11, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to SEQ ID NO;

16, a CDRL2 sequence that is at least 90% identical to SEQ ID NO;

20, and a CDRL3 sequence that is at least 90% identical to SEQ ID NO;

23;

ix) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

29 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

35;

x) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO;

29, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO;

29, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO;

29, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO;

35, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO;

35, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO;

35;

xi) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

73 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

74;

xii) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO;

73, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO;

73, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO;

73, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO;

74, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO;

74, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO;

74;

xiii) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

78 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

79;

xiv) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO;

78, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO;

78, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO;

78, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO;

79, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO;

79, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO;

79;

xv) a heavy chain variable region sequence that is at least 95% identical to SEQ ID NO;

83 and a light chain variable region sequence that is at least 95% identical to SEQ ID NO;

84;

or

xvi) a heavy chain variable region sequence comprising a CDRH1 sequence that is at least 90% identical to a CDRH1 sequence of SEQ ID NO;

83, a CDRH2 sequence that is at least 90% identical to a CDRH2 sequence of SEQ ID NO;

83, and a CDRH3 sequence that is at least 90% identical to a CDRH3 sequence of SEQ ID NO;

83, and a light chain variable region sequence comprising a CDRL1 sequence that is at least 90% identical to a CDRL1 sequence of SEQ ID NO;

84, a CDRL2 sequence that is at least 90% identical to a CDRL2 sequence of SEQ ID NO;

84, and a CDRL3 sequence that is at least 90% identical to a CDRL3 sequence of SEQ ID NO;

84.

2. The method of claim 1, further comprising a step of:

selecting the subject who is (i) suffering from a muscle condition or disorder;

(ii) suffering from, or at risk of developing, a metabolic disorder;

or both (i) and (ii).

3. The method of claim 1, wherein the subject has a muscle condition selected from the group consisting of:

myopathy, muscular atrophy, muscular dystrophy, and nerve injury.

4. The method of claim 3, wherein the muscular atrophy is associated with spinal muscular atrophy (SMA).

5. The method of claim 3, wherein the nerve injury comprises partial denervation of neurons that innervate muscle, or impaired signaling between a motor neuron and a target muscle.

6. The method of claim 3, wherein the muscular atrophy is associated with myotrophic lateral sclerosis (ALS).

7. The method of claim 3, wherein the muscular atrophy is associated with myasthenia gravis.

8. The method of claim 1, wherein the subject has a metabolic disease selected from the group consisting of type I diabetes, type II diabetes, obesity, metabolic syndrome/pre-diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), a hypo-metabolic state, double diabetes, Cushings disease, metabolic myopathies, androgen deficiency and an obesity syndrome.

9. The method of claim 8, wherein the metabolic myopathy is a glycogen storage diseases or a lipid storage disorder.

10. The method of claim 1, wherein the subject is treated with a second therapy.

11. The method of claim 10, wherein the second therapy comprises neuroprotective therapy or a stem cell therapy.