Anti-transthyretin antibodies

Patent metadata

Field	Value
Publication number	US-2018201670-A1
Application number	US-201815861600-A
Country	US
Kind code	A1
Filing date	Jan 3, 2018
Priority date	Jan 28, 2015
Publication date	Jul 19, 2018
Grant date	—

Abstract

The invention provides antibodies that specifically bind to transthyretin (TTR). The antibodies can be used for treating or effecting prophylaxis of diseases or disorders associated with TTR accumulation or accumulation of TTR deposits (e.g., TTR amyloidosis). The antibodies can also be used for diagnosing TTR amyloidosis and inhibiting or reducing aggregation of TTR, among other applications.

First claim

1 - 67 . (canceled)

68 . The method of claim 73 , wherein administering the antibody inhibits or reduces aggregation of transthyretin in the subject.

69 . The method of claim 73 , wherein administering the antibody inhibits or reduces transthyretin fibril formation in the subject.

70 . The method of claim 73 , wherein administering the antibody reduces transthyretin deposits in a subject.

71 . The method of claim 73 , wherein administering the antibody clears aggregated transthyretin in the subject relative to a subject having or at risk of developing a transthyretin-mediated amyloidosis who has not received the antibody.

72 . The method of claim 73 , wherein administering the antibody stabilizes a non-toxic conformation of transthyretin in the subject.

73 . A method of treating or effecting prophylaxis of a transthyretin-mediated amyloidosis in a subject, comprising administering to the subject an effective regime of an antibody that specifically binds transthyretin comprising three heavy chain CDRs and three light chain CDRs substantially from antibody 6C1.

74 . The method of claim 73 , wherein administering the antibody delays the onset of a transthyretin-mediated amyloidosis in the subject

75 . The method of claim 73 , wherein the transthyretin-mediated amyloidosis is associated with a condition selected from any of cardiomyopathy or hypertrophy, familial amyloid polyneuropathy, central nervous system selective amyloidosis (CNSA), senile systemic amyloidosis, senile cardiac amyloidosis, spinal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age related macular degeneration, and a ligament or tendon disorder.

76 . A method of treating a subject having or at risk of any of cardiomyopathy or hypertrophy, familial amyloid polyneuropathy, central nervous system selective amyloidosis (CNSA), senile systemic amyloidosis, senile cardiac amyloidosis, spinal stenosis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, age related macular degeneration, and a ligament or tendon disorder, the method comprising administering to the subject an effective regime of the antibody of an antibody that specifically binds transthyretin comprising three heavy chain CDRs and three light chain CDRs substantially from antibody 6C1.

77 - 94 . (canceled)

95 . The method of claim 73 , wherein the antibody comprises three Kabat heavy chain CDRs (SEQ ID NOS: 10-12, respectively) and three light CDRs (SEQ ID NOS: 18-20, respectively).

96 . The method of claim 95 , wherein the antibody has a human IgG1 isotype.

97 . The method of claim 73 , wherein the antibody is a humanized or chimeric 6C1 antibody that specifically binds to transthyretin, wherein 6C1 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO:1 and a mature light chain variable region of SEQ ID NO:13.

98 . The method of claim 73 , wherein the antibody comprises a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:9 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to SEQ ID NO:17.

99 . The method of claim 95 , provided position H77 of the antibody is occupied by T.

100 . The method of claim 99 , provided position H49 of the antibody is occupied by A.

101 . The method of claim 99 , provided positions H76 and H82(a) of the antibody are occupied by S.

102 . The method of claim 99 , provided positions H19, H44, H83, and H89 of the antibody are occupied by K, R, K, and M, respectively.

103 . The method of claim 95 , provided position L45 of the antibody is occupied by K.

104 . The method of claim 103 , provided position L2 of the antibody is occupied by V.

105 . The method of claim 98 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:9 and a mature light chain variable region having an amino acid sequence at least 95% identical to SEQ ID NO:17.

106 . The method of claim 105 , wherein the antibody comprises a mature heavy chain variable region having an amino acid sequence at least 98% identical to SEQ ID NO:9 and a mature light chain variable region having an amino acid sequence at least 98% identical to SEQ ID NO:17.

107 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:4.

108 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:5.

109 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:6.

110 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:7.

111 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:8.

112 . The method of claim 97 , wherein the mature heavy chain variable region of the antibody has the amino acid sequence of SEQ ID NO:9.

113 . The method of any one of claims 107 - 112 , wherein the mature light chain variable region of the antibody has the amino acid sequence of SEQ ID NO:16 or SEQ ID NO:17.

114 . The method of claim 73 , wherein the mature heavy chain has the amino acid sequence of SEQ ID NO: 9 and the mature light chain variable region of the antibody has an amino acid sequence of SEQ ID NO:17.

115 . The method of claim 73 or 106 , wherein the antibody is a binding fragment.

116 . The method of claim 115 , wherein the binding fragment is a single-chain antibody, Fab, or Fab′2 fragment.

117 . The method of claim 73 or 106 , wherein the mature light chain variable region of the antibody is fused to a light chain constant region and the mature heavy chain variable region of the antibody is fused to a heavy chain constant region.

118 . The method of claim 117 , wherein the heavy chain constant region is a mutant form of a natural human heavy chain constant region which has reduced binding to a Fcγ receptor relative to the natural human heavy chain constant region.

119 . The method of claim 117 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the sequence of SEQ ID NO:26 and/or the mature light chain variable region is fused to a light chain constant region having the sequence of SEQ ID NO:28.

Assignees

• Prothena Biosciences Ltd
• Univ Health Network

Inventors

• Nijjar Tarlochan S
• Chakrabartty Avijit
• Higaki Jeffrey N

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/567

  Framework region [FR] · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title