Claims for Patent: 10,323,083

Summary for Patent: 10,323,083

Title:	Agents that specifically bind matrilin-3 and their use
Abstract:	Monoclonal antibodies and antibody fragments that specifically bind to matrilin-3, conjugates including these molecules, and nucleic acid molecules encoding the antibodies, antigen binding fragments and conjugates, are disclosed. Also disclosed are compositions including the disclosed antibodies, antigen binding fragments, conjugates, and nucleic acid molecules. Methods of treating or inhibiting a cartilage disorder in a subject, as well as methods of increasing chondrogenesis in cartilage tissue are further provided. The methods can be used, for example, for treating or inhibiting a growth plate disorder in a subject, such as a skeletal dysplasia or short stature.
Inventor(s):	Baron; Jeffrey (Bethesda, MD), Cheung; Crystal Sao Fong (Bethesda, MD), Lui; Julian Chun Kin (Bethesda, MD), Dimitrov; Dimiter (Frederick, MD), Zhu; Zhongyu (Frederick, MD)
Assignee:	The United States of America, as represented by the Secretary, Department of Health and Human Services (Washington, DC)
Application Number:	15/111,773
Patent Claims:	1. An isolated monoclonal antibody, comprising a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3, and a light chain variable region comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a L-CDR3, of the amino acid sequences set forth as: SEQ ID NO: 5 and SEQ ID NO: 6, respectively (clone 26); and wherein the monoclonal antibody specifically binds to matrilin-3. 2. The isolated monoclonal antibody of claim 1, wherein: the heavy chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 5 and comprises the CDR sequences of SEQ ID NO: 5; the light chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 6 and comprises the CDR sequences of SEQ ID NO: 6; or the heavy chain variable region and the light chain variable region comprise amino acid sequences at least 80% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and comprise the CDR sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 3. The antibody of claim 1, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 5. 4. The antibody of claim 1, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 6. 5. The antibody of claim 1, wherein the heavy and light chain variable regions comprise the amino acid sequences set forth as: SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 6. The antibody of claim 1, comprising a human framework region. 7. The antibody of claim 1, wherein the antibody is an IgG. 8. The antibody of claim 1, conjugated to a heterologous detectable marker. 9. The antibody of claim 8, wherein the detectable marker is a fluorescent, enzymatic, heavy metal, or radioactive marker. 10. The antibody of claim 1, conjugated to a heterologous effector molecule. 11. The antibody of claim 10, wherein the effector molecule is a chondrogenic agent. 12. The antibody of claim 11, wherein the chondrogenic agent is one of a growth hormone, an insulin-like growth factor-1, an Indian hedgehog, a bone morphogenetic protein, a C-type natriuretic protein, or a Wnt protein, or a biologically active fragment thereof that induces chondrogenesis; or a steroid. 13. The antibody of claim 12, wherein the chondrogenic agent is insulin-like growth factor-1. 14. A method of increasing chondrogenesis in cartilage tissue, comprising: contacting cartilage tissue with a therapeutically effective amount of the antibody conjugated to the chondrogenic agent of claim 11 under conditions sufficient to form an immune complex, thereby increasing chondrogenesis in the cartilage tissue. 15. A method of targeting a chondrogenic agent to cartilage tissue in a subject, comprising: administering to the subject an amount of the antibody conjugated to the chondrogenic agent of claim 11 under conditions sufficient to form an immune complex, wherein formation of the immune complex targets the chondrogenic agent to the cartilage tissue in the subject. 16. The method of claim 15, wherein the subject has a cartilage disorder. 17. The method of claim 16, wherein the cartilage disorder is a skeletal dysplasia. 18. The method of claim 17, wherein the skeletal dysplasia is achondroplasia, hypochondroplasia, or short stature homeobox gene (SHOX) deficiency. 19. The method of claim 16, wherein the cartilage disorder is osteoarthritis. 20. The method of claim 16, wherein the method comprises an increase in linear growth of the subject compared to a control treatment. 21. The method of claim 16, wherein the method comprises an increase in chondrogenesis in the subject compared to a control treatment. 22. The method of claim 15, wherein the subject has short stature. 23. The method of claim 22, wherein the short stature is idiopathic short stature, short stature due to systemic disease, short stature associated with a dysmorphic syndrome, short stature due to chromosomal abnormalities, iatrogenic short stature, short stature due to radiation or medications, short stature in children born small for gestational age, and short stature due to undernutrition. 24. The antibody of claim 10, wherein the effector molecule is an anti-arthritis agent. 25. The antibody of claim 24, wherein the anti-arthritis agent is a parathyroid hormone (PTH) or biologically active fragment thereof. 26. A method of targeting an effector molecule to cartilage tissue in a subject, comprising: administering to the subject an amount of the antibody conjugated to the effector molecule of claim 10 under conditions sufficient to form an immune complex, wherein formation of the immune complex targets the effector molecule to the cartilage tissue in the subject. 27. The method of claim 26, wherein the subject has arthritis. 28. The method of claim 27, wherein the subject has osteoarthritis. 29. The method of claim 26, wherein the subject has a cartilage disorder. 30. The method of claim 29, wherein the cartilage disorder is a skeletal dysplasia. 31. The method of claim 30, wherein the skeletal dysplasia is achondroplasia, hypochondroplasia, or short stature homeobox gene (SHOX) deficiency. 32. The method of claim 29, wherein the subject has short stature. 33. A composition, comprising a pharmaceutically acceptable carrier and an the antibody of claim 1. 34. A kit for treating a cartilage disorder in a subject, comprising a container comprising the antibody of claim 1, and instructions for using the kit. 35. An isolated monoclonal antibody, comprising: a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR1), a HCDR2, and a HCDR3 comprising the amino acid sequences set forth as residues 26-33, 51-58, 97-108 of SEQ ID NO: 5, respectively, and a light chain variable region comprising a light chain complementarity determining region (LCDR1), a LCDR2, and a LCDR3 comprising the amino acid sequence set forth as residues 26-33, 51-53, and 90-100 of SEQ ID NO: 6, respectively; wherein the monoclonal antibody specifically binds to matrilin-3. 36. The monoclonal antibody of claim 35, wherein: the heavy chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 5 and comprises the CDR sequences of SEQ ID NO: 5; the light chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 6 and comprises the CDR sequences of SEQ ID NO: 6; or the heavy chain variable region and the light chain variable region comprise amino acid sequences at least 80% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and comprise the CDR sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 37. The monoclonal antibody of claim 35, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 5. 38. The monoclonal antibody of claim 35, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 6. 39. The monoclonal antibody of claim 35, comprising a human framework region. 40. The monoclonal antibody of claim 35, wherein the antibody is an IgG. 41. The monoclonal antibody of claim 35, conjugated to a heterologous detectable marker. 42. The monoclonal antibody of claim 35, wherein the detectable marker is a fluorescent, enzymatic, heavy metal, or radioactive marker. 43. The monoclonal antibody of claim 35, conjugated to a heterologous effector molecule. 44. The monoclonal antibody of claim 43, wherein the effector molecule is a chondrogenic agent. 45. The monoclonal antibody of claim 44, wherein the chondrogenic agent is one of a growth hormone, an insulin-like growth factor-1, an Indian hedgehog, a bone morphogenetic protein, a C-type natriuretic protein, or a Wnt protein, or a biologically active fragment thereof that induces chondrogenesis; or a steroid. 46. The monoclonal antibody of claim 45, wherein the chondrogenic agent is insulin-like growth factor-1. 47. The monoclonal antibody of claim 43, wherein the effector molecule is an anti-arthritis agent. 48. The monoclonal antibody of claim 47, wherein the anti-arthritis agent is a parathyroid hormone (PTH) or biologically active fragment thereof. 49. A kit for treating a cartilage disorder in a subject, comprising a container comprising the antibody of claim 35, and instructions for using the kit. 50. An antigen binding molecule, comprising: a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3, and a light chain variable region comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3, of the amino acid sequences set forth as SEQ ID NO: 5 and SEQ ID NO: 6, respectively; and wherein the antigen binding molecule specifically binds to matrilin-3. 51. The antigen binding molecule of claim 50, wherein the antigen binding molecule is a Fv, a Fab, a F(ab').sub.2, an scFv, or an scFV.sub.2. 52. A conjugate, comprising the antigen binding molecule of claim 50 linked to a chondrogenic agent or an anti-arthritis agent. 53. The conjugate of claim 52, further comprising an Fc domain. 54. The conjugate of claim 53, comprising, from N- to C-terminus, the chondrogenic agent, the antigen binding molecule, and the Fc domain; or the chondrogenic agent, the Fc domain, and the antigen binding molecule. 55. The conjugate of claim 52, wherein the antigen binding molecule is an scFv. 56. The conjugate of claim 52, wherein: (a) the chondrogenic agent is IGF-1; (b) the antigen binding molecule is an scFv; (c) the conjugate comprises an Fc domain, and the Fc domain is an Fc IgG domain that can form a dimer under physiological conditions; (d) the conjugate comprises an Fc domain, and the Fc domain is a mutant Fc IgG domain that does not dimerize under physiological conditions; or (e) a combination of two or more of (a), (b), and (c), or a combination of two or more of (a), (b), and (d). 57. The conjugate of claim 56, wherein (a) the IGF-1 comprises the amino acid sequence set forth as SEQ ID NO: 49 (b) the scFv comprises the amino acid sequence set forth as SEQ ID NO: 12; (c) the Fc domain comprises the amino acid sequence set forth as SEQ ID NO: 47; (d) the Fc domain comprises the amino acid sequence set forth as SEQ ID NO: 48 respectively. 58. The conjugate of claim 57, comprising an amino acid sequence set forth as SEQ ID NO: 43 or SEQ ID NO: 46. 59. The antigen binding molecule of claim 50, wherein: the heavy chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 5 and comprises the CDR sequences of SEQ ID NO: 5; the light chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 6 and comprises the CDR sequences of SEQ ID NO: 6; or the heavy chain variable region and the light chain variable region comprise amino acid sequences at least 80% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and comprise the CDR sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 60. The antigen binding molecule of claim 50, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 5. 61. The antigen binding molecule of claim 50, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 6. 62. The antigen binding molecule of claim 50, wherein the heavy and light chain variable regions comprise the amino acid sequences set forth as SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 63. The antigen binding molecule of claim 50, comprising a human framework region. 64. The antigen binding molecule of claim 50, conjugated to a heterologous detectable marker. 65. The antigen binding molecule of claim 64, wherein the detectable marker is a fluorescent, enzymatic, heavy metal, or radioactive marker. 66. The antigen binding molecule of claim 50, conjugated to a heterologous effector molecule. 67. The antigen binding molecule of claim 66, wherein the effector molecule is a chondrogenic agent. 68. The antigen binding molecule of claim 67, wherein the chondrogenic agent is one of a growth hormone, an insulin-like growth factor-1, an Indian hedgehog, a bone morphogenetic protein, a C-type natriuretic protein, or a Wnt protein, or a biologically active fragment thereof that induces chondrogenesis; or a steroid. 69. The antigen binding molecule of claim 68, wherein the chondrogenic agent is insulin-like growth factor-1. 70. The antigen binding molecule of claim 66, wherein the effector molecule is an anti-arthritis agent. 71. The antigen binding molecule of claim 70, wherein the anti-arthritis agent is a parathyroid hormone (PTH) or biologically active fragment thereof. 72. An antigen binding molecule of an antibody, comprising: a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR1), a HCDR2, and a HCDR3 comprising the amino acid sequences set forth as residues 26-33, 51-58, 97-108 of SEQ ID NO: 5, respectively, and the a light chain variable region comprising a light chain complementarity determining region (LCDR1), a LCDR2, and a LCDR3 comprising the amino acid sequence set forth as residues 26-33, 51-53, and 90-100 of SEQ ID NO: 6, respectively; and wherein the antigen binding molecule specifically binds to matrilin-3. 73. The antigen binding molecule of claim 72, wherein: the heavy chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 5 and comprises the CDR sequences of SEQ ID NO: 5; the light chain variable region comprises an amino acid sequence at least 80% identical to SEQ ID NO: 6 and comprises the CDR sequences of SEQ ID NO: 6; or the heavy chain variable region and the light chain variable region comprise amino acid sequences at least 80% identical to SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and comprise the CDR sequences of SEQ ID NO: 5 and SEQ ID NO: 6, respectively. 74. The antigen binding molecule of claim 72, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 5. 75. The antigen binding molecule of claim 72, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 6. 76. The antigen binding molecule of claim 72, comprising a human framework region. 77. The antigen binding molecule of claim 72, wherein the antigen binding molecule is a Fv, a Fab, a F(ab').sub.2, an scFv, or an scFV.sub.2 fragment. 78. The antigen binding molecule of claim 72, conjugated to a heterologous detectable marker. 79. The antigen binding molecule of claim 78, wherein the detectable marker is a fluorescent, enzymatic, heavy metal, or radioactive marker. 80. The antigen binding molecule of claim 72, conjugated to a heterologous effector molecule. 81. The antigen binding molecule of claim 80, wherein the effector molecule is a chondrogenic agent. 82. The antigen binding molecule of claim 81, wherein the chondrogenic agent is one of a growth hormone, an insulin-like growth factor-1, an Indian hedgehog, a bone morphogenetic protein, a C-type natriuretic protein, or a Wnt protein, or a biologically active fragment thereof that induces chondrogenesis; or a steroid. 83. The antigen binding molecule of claim 82, wherein the chondrogenic agent is insulin-like growth factor-1. 84. The antigen binding molecule of claim 80, wherein the effector molecule is an anti-arthritis agent. 85. The antigen binding molecule of claim 84, wherein the anti-arthritis agent is a parathyroid hormone (PTH) or biologically active fragment thereof. 86. A method of targeting an effector molecule to cartilage tissue in a subject, comprising: administering to the subject an amount of the antigen binding molecule conjugated to the effector molecule of claim 80 under conditions sufficient to form an immune complex, wherein formation of the immune complex targets the effector molecule to the cartilage tissue in the subject. 87. The method of claim 86, wherein the subject has arthritis. 88. The method of claim 87, wherein the subject has osteoarthritis. 89. The method of claim 86, wherein the subject has a cartilage disorder. 90. The method of claim 89, wherein the cartilage disorder is a skeletal dysplasia. 91. The method of claim 90, wherein the skeletal dysplasia is achondroplasia, hypochondroplasia, or short stature homeobox gene (SHOX) deficiency. 92. The method of claim 90, wherein the subject has short stature. 93. A conjugate, comprising the antigen binding molecule of claim 72 linked to a chondrogenic agent or an anti-arthritis agent. 94. The conjugate of claim 93, further comprising an Fc domain. 95. The conjugate of claim 94, comprising, from N- to C-terminus, the chondrogenic agent, the antigen binding molecule, and the Fc domain; or the chondrogenic agent, the Fc domain, and the antigen binding molecule. 96. The conjugate of claim 93, wherein the antigen binding molecule is an scFv. 97. The conjugate of claim 93, wherein: (a) the chondrogenic agent is IGF-1; (b) the antigen binding molecule is an scFv; (c) conjugate comprises an Fc domain, wherein the Fc domain is an Fc IgG domain that can form a dimer under physiological conditions; (d) the conjugate comprises an Fc domain, wherein the Fc domain is a mutant Fc IgG domain that does not dimerized under physiological conditions; or (e) a combination of two or more of (a), (b), and (c), or a combination of two or more of (a), (b), and (d). 98. A single chain variable molecule (scFv) comprising the amino acid sequence set forth as SEQ ID NO: 12, wherein the scFv specifically binds to matrilin-3.

Details for Patent 10,323,083

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2034-01-15