COMPOSITIONS AND METHODS FOR INCREASING MUSCLE GROWTH

• US 20160031993A1
• Filed: 07/23/2015
• Published: 02/04/2016
• Est. Priority Date: 04/27/2009
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Berger, Catrin, Herrmann, Tanja, Lu, Chris, Sheppard, Kelly-Ann, Trifilieff, Estelle, Urlinger, Stephanie
• Application Number:
  US14/806,997
• Publication Number:
  US 20160031993A1
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07H 21/04 : with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• 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

This disclosure is in the field of anti-Activin receptor IIB (ActRIIB) antibodies. In particular, it relates to the use of said antibodies for treating muscle disorders, such as muscle wasting due to disease or disuse.

Claims

1. An anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:

181.

2. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, which binds to ActRIIB with a K_D of 1 nM or less.

3. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof inhibits myostatin binding to ActRIIB.

4. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof inhibits myostatin induced signalling as measured by a Smad dependent reporter gene assay.

5. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof binds to ActRIIB with a 10-fold or greater affinity than it binds to ActRIIA.

6. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises at least one complementarity determining region having at least 95% identity to at least one of the CDRs recited in SEQ ID NOs:

9, 18-28, 37, 51, 65, 71-75 or 79.

7. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises at least one complementarity determining region having at least 95% identity to CDR3 recited in SEQ ID NOs:

37.

8. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises a VH polypeptide sequence having at least 95% sequence identity to at least one of the sequences of SEQ ID NOs:

99-112.

9. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises a VL polypeptide sequence having at least 95% sequence identity to at least one of the sequences of SEQ ID NOs:

85-98.

10. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises a VH polypeptide sequence having at least 95% sequence identity to at least one of the sequences of SEQ ID NOs:

99-112 and a VL polypeptide sequence having at least 95% sequence identity to at least one of the sequences of SEQ ID NOs;

85-98.

11. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof comprises:

a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NOs;

9;

a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs;

18-28;

a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO;

37;

a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NOs;

51;

a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NOs;

65; and

a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs;

71-79.

13. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment comprises a full length heavy chain amino acid sequence having at least 95% sequence identity to at least one sequence selected from the group consisting of SEQ ID NOs:

146-150 and 156-160.

14. The antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment comprises a full length light chain amino acid sequence having at least 95% sequence identity to at least one sequence selected from the group consisting of SEQ ID NOs:

141-145 and 151-155.

19. An antibody according to claim 1 which binds to an epitope comprising or consisting of:

(a) amino acids 78-83 of SEQ ID NO;

181 (WLDDFN—

SEQ ID NO;

188);

(b) amino acids 76-84 of SEQ ID NO;

181 (GCWLDDFNC—

SEQ ID NO;

186);

(c) amino acids 75-85 of SEQ ID NO;

181 (KGCWLDDFNCY—

SEQ ID NO;

190);

(d) amino acids 52-56 of SEQ ID NO;

181 (EQDKR—

SEQ ID NO;

189);

(e) amino acids 49-63 of SEQ ID NO;

181 (CEGEQDKRLHCYASW—

SEQ ID NO;

187);

or

(f) amino acids 78-83 of SEQ ID NO;

181 (WLDDFN) and amino acids 52-56 of SEQ ID NO;

181 (EQDKR).

21. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, wherein said antibody or functional fragment thereof is of the IgG1 isotype.

22. The anti-ActRIIB antibody or functional fragment thereof according to claim 1, which has altered effector function through mutation of the Fc region.

23. An isolated polynucleotide sequence encoding an antibody or functional fragment thereof according to claim 1.

24. An isolated polynucleotide sequence according to claim 23, comprising one or more of SEQ ID NOs:

113-140 or 161-180.

25. A cloning or expression vector comprising one or more isolated polynucleotide sequences according to claim 23.

26. A vector according to claim 25, wherein said vector comprises one or more of SEQ ID NOs:

113-140 or 161-180, or fragment thereof encoding at least one CDR region.

27. An isolated host cell comprising one or more vectors according to claim 25.

28. A process for the production of an anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:

181, comprising culturing the host cell of claim 27 and isolating said antibody or functional fragment thereof.

29. A pharmaceutical composition comprising an anti-ActRIIB antibody or functional fragment thereof of claim 1 or a polynucleotide sequence encoding an anti-ActRIIB antibody or functional fragment thereof of claim 1.

30. A pharmaceutical composition according to claim 29, further comprising a pharmaceutically acceptable diluent or carrier.

31. A pharmaceutical composition according to claim 29, further comprising one or more additional active agents.

32. A pharmaceutical composition according to claim 31, wherein said one or more additional active agents is selected from IGF-1, IGF-2, a variant of IGF-1 or IGF-2, an anti-myostatin antibody, a myostatin propeptide, a myostatin decoy protein that binds ActRIIB but does not activate it, a beta 2 agonist, a Ghrelin agonist, a SARM, GH agonists/mimetics and follistatin.

38. A method of ameliorating the muscle wasting effects of enforced inactivity or time spent in a zero gravity environment comprising administering an effective dose of an antibody or functional fragment thereof according to claim 1 prior to said period of enforced inactivity or time spent in a zero gravity environment.

12. An anti-ActRIIB antibody or functional fragment thereof comprising:

(a) a heavy chain variable region CDR1 of SEQ ID NO;

1;

a heavy chain variable region CDR2 of SEQ ID NO;

15;

a heavy chain variable region CDR3 of SEQ ID NO;

29;

a light chain variable region CDR1 of SEQ ID NO;

43;

a light chain variable region CDR2 of SEQ ID NO;

57; and

a light chain variable region CDR3 of SEQ ID NO;

71,

(b) a heavy chain variable region CDR1 of SEQ ID NO;

2 a heavy chain variable region CDR2 of SEQ ID NO;

16;

a heavy chain variable region CDR3 of SEQ ID NO;

30;

a light chain variable region CDR1 of SEQ ID NO;

44;

a light chain variable region CDR2 of SEQ ID NO;

58; and

a light chain variable region CDR3 of SEQ ID NO;

72,

(c) a heavy chain variable region CDR1 of SEQ ID NO;

3;

a heavy chain variable region CDR2 of SEQ ID NO;

17;

a heavy chain variable region CDR3 of SEQ ID NO;

31;

a light chain variable region CDR1 of SEQ ID NO;

45;

a light chain variable region CDR2 of SEQ ID NO;

59; and

a light chain variable region CDR3 of SEQ ID NO;

73,

(d) a heavy chain variable region CDR1 of SEQ ID NO;

4;

a heavy chain variable region CDR2 of SEQ ID NO;

18;

a heavy chain variable region CDR3 of SEQ ID NO;

32;

a light chain variable region CDR1 of SEQ ID NO;

46;

a light chain variable region CDR2 of SEQ ID NO;

60; and

a light chain variable region CDR3 of SEQ ID NO;

74,

(e) a heavy chain variable region CDR1 of SEQ ID NO;

5;

a heavy chain variable region CDR2 of SEQ ID NO;

19;

a heavy chain variable region CDR3 of SEQ ID NO;

33;

a light chain variable region CDR1 of SEQ ID NO;

47;

a light chain variable region CDR2 of SEQ ID NO;

61; and

a light chain variable region CDR3 of SEQ ID NO;

75,

(f) a heavy chain variable region CDR1 of SEQ ID NO;

6;

a heavy chain variable region CDR2 of SEQ ID NO;

20;

a heavy chain variable region CDR3 of SEQ ID NO;

34;

a light chain variable region CDR1 of SEQ ID NO;

48;

a light chain variable region CDR2 of SEQ ID NO;

62; and

a light chain variable region CDR3 of SEQ ID NO;

76,

(g) a heavy chain variable region CDR1 of SEQ ID NO;

7;

a heavy chain variable region CDR2 of SEQ ID NO;

21;

a heavy chain variable region CDR3 of SEQ ID NO;

35;

a light chain variable region CDR1 of SEQ ID NO;

49;

a light chain variable region CDR2 of SEQ ID NO;

63; and

a light chain variable region CDR3 of SEQ ID NO;

77,

(h) a heavy chain variable region CDR1 of SEQ ID NO;

8;

a heavy chain variable region CDR2 of SEQ ID NO;

22;

a heavy chain variable region CDR3 of SEQ ID NO;

36;

a light chain variable region CDR1 of SEQ ID NO;

50 a light chain variable region CDR2 of SEQ ID NO;

64; and

a light chain variable region CDR3 of SEQ ID NO;

78,

(i) a heavy chain variable region CDR1 of SEQ ID NO;

9;

a heavy chain variable region CDR2 of SEQ ID NO;

23;

a heavy chain variable region CDR3 of SEQ ID NO;

37;

a light chain variable region CDR1 of SEQ ID NO;

51;

a light chain variable region CDR2 of SEQ ID NO;

65; and

a light chain variable region CDR3 of SEQ ID NO;

79,

(j) a heavy chain variable region CDR1 of SEQ ID NO;

10;

a heavy chain variable region CDR2 of SEQ ID NO;

24;

a heavy chain variable region CDR3 of SEQ ID NO;

38;

a light chain variable region CDR1 of SEQ ID NO;

52;

a light chain variable region CDR2 of SEQ ID NO;

66; and

a light chain variable region CDR3 of SEQ ID NO;

80,

(k) a heavy chain variable region CDR1 of SEQ ID NO;

11;

a heavy chain variable region CDR2 of SEQ ID NO;

25;

a heavy chain variable region CDR3 of SEQ ID NO;

39;

a light chain variable region CDR1 of SEQ ID NO;

53;

a light chain variable region CDR2 of SEQ ID NO;

67; and

a light chain variable region CDR3 of SEQ ID NO;

81,

(l) a heavy chain variable region CDR1 of SEQ ID NO;

12;

a heavy chain variable region CDR2 of SEQ ID NO;

26;

a heavy chain variable region CDR3 of SEQ ID NO;

40;

a light chain variable region CDR1 of SEQ ID NO;

54;

a light chain variable region CDR2 of SEQ ID NO;

68; and

a light chain variable region CDR3 of SEQ ID NO;

82,

(m) a heavy chain variable region CDR1 of SEQ ID NO;

13;

a heavy chain variable region CDR2 of SEQ ID NO;

27;

a heavy chain variable region CDR3 of SEQ ID NO;

41;

a light chain variable region CDR1 of SEQ ID NO;

55;

a light chain variable region CDR2 of SEQ ID NO;

69; and

a light chain variable region CDR3 of SEQ ID NO;

83, or

(n) a heavy chain variable region CDR1 of SEQ ID NO;

14;

a heavy chain variable region CDR2 of SEQ ID NO;

28;

a heavy chain variable region CDR3 of SEQ ID NO;

42;

a light chain variable region CDR1 of SEQ ID NO;

56;

a light chain variable region CDR2 of SEQ ID NO;

70; and

a light chain variable region CDR3 of SEQ ID NO;

84.

15. An anti-ActRIIB antibody or functional fragment comprising:

(a) the variable light chain sequence of SEQ ID NO;

85 and variable heavy chain sequence of SEQ ID NO;

99;

(b) the variable light chain sequence of SEQ ID NO;

86 and variable heavy chain sequence of SEQ ID NO;

100;

(c) the variable light chain sequence of SEQ ID NO;

87 and variable heavy chain sequence of SEQ ID NO;

101;

(d) the variable light chain sequence of SEQ ID NO;

88 and variable heavy chain sequence of SEQ ID NO;

102;

(e) the variable light chain sequence of SEQ ID NO;

89 and variable heavy chain sequence of SEQ ID NO;

103;

(f) the variable light chain sequence of SEQ ID NO;

90 and variable heavy chain sequence of SEQ ID NO;

104;

(g) the variable light chain sequence of SEQ ID NO;

91 and variable heavy chain sequence of SEQ ID NO;

105;

(h) the variable light chain sequence of SEQ ID NO;

92 and variable heavy chain sequence of SEQ ID NO;

106;

(i) the variable light chain sequence of SEQ ID NO;

93 and variable heavy chain sequence of SEQ ID NO;

107;

(j) the variable light chain sequence of SEQ ID NO;

94 and variable heavy chain sequence of SEQ ID NO;

108;

(k) the variable light chain sequence of SEQ ID NO;

95 and variable heavy chain sequence of SEQ ID NO;

109;

(l) the variable light chain sequence of SEQ ID NO;

96 and variable heavy chain sequence of SEQ ID NO;

110;

(m) the variable light chain sequence of SEQ ID NO;

97 and variable heavy chain sequence of SEQ ID NO;

111;

or

(n) the variable light chain sequence of SEQ ID NO;

98 and variable heavy chain sequence of SEQ ID NO;

112.

16. An anti-ActRIIB antibody or functional fragment comprising:

(a) the heavy chain sequence of SEQ ID NO;

146 and light chain sequence of SEQ ID NO;

141;

(b) the heavy chain sequence of SEQ ID NO;

147 and light chain sequence of SEQ ID NO;

142;

(c) the heavy chain sequence of SEQ ID NO;

148 and light chain sequence of SEQ ID NO;

143;

(d) the heavy chain sequence of SEQ ID NO;

149 and light chain sequence of SEQ ID NO;

144;

(e) the heavy chain sequence of SEQ ID NO;

150 and light chain sequence of SEQ ID NO;

145;

(f) the heavy chain sequence of SEQ ID NO;

156 and light chain sequence of SEQ ID NO;

151;

(g) the heavy chain sequence of SEQ ID NO;

157 and light chain sequence of SEQ ID NO;

152;

(h) the heavy chain sequence of SEQ ID NO;

158 and light chain sequence of SEQ ID NO;

153;

(i) the heavy chain sequence of SEQ ID NO;

159 and light chain sequence of SEQ ID NO;

154;

or

(j) the heavy chain sequence of SEQ ID NO;

160 and light chain sequence of SEQ ID NO;

155.

17. An anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:

181, wherein the antibody or functional fragment thereof cross-blocks or is cross-blocked from binding to ActRIIB by at least one antibody or functional fragment thereof of claim 16.

18. An anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:

181, wherein the antibody or functional fragment thereof cross-blocks or is cross-blocked by at least one antibody of claim 17 from binding to ActRIIB.

20. The antibody or functional fragment thereof of claim 17, wherein cross-blocking or binding is detected in a BIAcore assay or an ELISA.

33. A method of treatment of a disease in an individual in need thereof, comprising the step of administering an effective dose of an anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO:

181, or a polynucleotide encoding an anti-ActRIIB antibody or functional fragment thereof that binds to ActRIIB between amino acids 19-134 of SEQ ID NO;

181,

wherein the disease is selected from;

a musculoskeletal disease or disorder;

acute and/or chronic renal disease or failure;

liver fibrosis or cirrhosis;

cancer such as breast cancer;

Parkinson'"'"'s Disease;

conditions associated with neuronal death, such as ALS, brain atrophy, or dementia and anemia;

liver, kidney and pulmonary fibrosis;

age-related conditions; and

cancers examplified by but not restricted to rhabdomyosarcomas, bone-loss inducing cancers, hepatocellular carcinomas, and gastrointestinal cancers.

34. The method of claim 33, wherein said musculoskeletal disease or disorder is muscle atrophy, myopathy, myotonia, a congenital myopathy, nemalene myopathy, multi/minicore myopathy and myotubular (centronuclear) myopathy, mitochondrial myopathy, familial periodic paralysis, inflammatory myopathy, metabolic myopathy, a glycogen or lipid storage disease, dermatomyositisis, polymyositis, inclusion body myositis, myositis ossificans, rhabdomyolysis and myoglobinurias;

a dystrophy, Duchenne, Becker, myotonic, fascioscapulohumeral, Emery-Dreifuss, oculopharyngeal, scapulohumeral, limb girdle, Fukuyama, or a congenital muscular dystrophy, or hereditary distal myopathy;

osteoporosis;

a bone fracture;

short stature;

dwarfism;

prolonged bed rest;

voluntary inactivity; and

/or involuntary inactivity.

35. The method according to claim 33, wherein the individual has been pre-treated with IGF-1, IGF-2 or variants of IGF-1 or IGF-2, an anti-myostatin antibody, a myostatin propeptide, a myostatin decoy protein that binds ActRIIB but does not activate it, a beta 2 agonist, a Ghrelin agonist, a SARM, GH agonists/mimetics or follistatin.

36. The method according to claim 33, wherein the individual has previously been refractive to treatment with IGF-1, IGF-2 or variants of IGF-1 or IGF-2, an anti-myostatin antibody, a myostatin propeptide, a myostatin decoy protein that binds ActRIIB but does not activate it, a beta 2 agonist, a Ghrelin agonist, a SARM, GH agonists/mimetics or follistatin.

37. The method according to claim 33, wherein the individual is elderly, has spent time in a zero gravity environment or has undergone a period of inactivity.

39. The method according to claim 33, wherein the individual has a fracture to a limb or joint.

40. The method according to claim 33, wherein the individual has undergone or is about to undergo, hip or knee replacement surgery.

41. An antibody encoded by pBW522 (DSM22873) or pBW524 (DSM2287).