Transthyretin antibodies and uses thereof

• US 9,790,269 B2
• Filed: 02/07/2014
• Issued: 10/17/2017
• Est. Priority Date: 02/08/2013
• Status: Active Grant

• Current Assignee: Protego Biopharma, Inc.
• Original Assignee: Misfolding Diagnostics, Inc.
• Inventors: Jiang, Xin, Kelly, Jeffery W., Chapman, Justin
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US14/760,194
• Publication Number:
  US 20160039916A1
• Time in Patent Office: 1,348 Days
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 against material from animals or humans
• 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 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The present invention provides compositions comprising anti-transthyretin antibodies. The compositions are particularly useful for diagnosis, prognosis and/or treatment of amyloid diseases or symptoms thereof.

Claims

1. An anti-transthyretin (TTR) monoclonal antibody that exhibits selective binding to non-native TTR under physiologically relevant conditions as compared to tetrameric TTR for said antibody binding, wherein the monoclonal antibody binds to an epitope consisting essentially of amino acid residues 49-61 or 109-121 in SEQ ID. No. 1 with a Kd equal to or less than 1 nM, wherein the epitope has a length of 10, 11, 12, 13, 14, 15, or 16 amino acids.

2. The antibody of claim 1, wherein said antibody binds to an epitope that is more accessible on non-native TTR as compared to tetrameric TTR, wherein epitope accessibility is evidenced by formation of an epitope/antibody complex in a binding assay.

3. The antibody of claim 1, wherein the monoclonal antibody binds to an epitope consisting essentially of amino acid residues 49-61 in SEQ ID. No 1.

4. The antibody of claim 1, wherein said antibody binds to wild-type monomeric and/or wild-type oligomeric TTR.

5. The antibody of claim 1, wherein said antibody binds to mutant monomeric and/or mutant oligomeric TTR.

6. The antibody of claim 1, wherein the monoclonal antibody binds to an epitope consisting essentially of amino acid residues 109-121 in SEQ ID. No 1.

7. The antibody of claim 1, wherein said antibody exhibits weaker binding to said epitope when TTR is in a native tetrameric conformation as compared to when TTR is in a non-native conformation.

8. The antibody of claim 7, wherein said weaker binding is ascertained by indirect ELISA.

9. The antibody of claim 1, wherein said monoclonal antibodies exhibit at least 100 times greater affinity towards the non-native TTR as compared to the tetrameric TTR.

10. The antibody of claim 9, wherein said antibody exhibits a Kd equal to or less than 1 nM, and wherein said monoclonal antibodies exhibit at least 100 times greater affinity towards the non-native TTR as compared to the tetrameric TTR.

11. A host cell that produces the antibody of claim 1.

12. The antibody of claim 1, wherein the antibody exhibits selective binding to a non-native form of mutant transthyretin (TTR) present in an amyloid disease carrier under physiologically relevant conditions as compared to a tetrameric form of said mutant TTR.

13. The antibody of claim 12, wherein said amyloid disease is familial amyloid neuropathy, familial amyloid cardiomyopathy, carpel tunnel syndrome, leptomeningeal amyloidosis, familial oculoleptomeningeal amyloidosis, or senile systemic amyloidosis.

14. The antibody of claim 12, wherein said mutant transthyretin comprises a mutation selected from the group consisting of a Cys10Arg mutation, a Leu12Pro mutation, an Asp18Glu mutation, an Asp18Gly mutation, an Asp18Asn mutation, a Val20Ile mutation, a Ser23Asn mutation, a Pro24Ser mutation, an Ala25Thr mutation, an Ala25Ser mutation, a Val28Met mutation, a Val30Met mutation, a Val30Ala mutation, a Val30Leu mutation, a Val30Gly mutation, a Val32Ala mutation, a Phe33Ile mutation, a Phe33Leu mutation, a Phe33Val mutation, a Phe33Cys mutation, an Arg34Thr mutation, an Arg34Gly mutation, a Lys35Asn mutation, a Lys35Thr mutation, an Ala36Pro mutation, an Asp38Ala mutation, an Asp38Val mutation, a Trp41Leu mutation, a Glu42Gly mutation, a Glu42Asp mutation, a Phe44Ser mutation, an Ala45Asp mutation, an Ala45Ser mutation, an Ala45Thr mutation, a Gly47Arg mutation, a Gly47Ala mutation, a Gly47Val mutation, a Gly47Glu mutation, a Thr49Ala mutation, a Thr49Ile mutation, a Thr49Pro mutation, a Ser50Arg mutation, a Ser50Ile mutation, a Glu51Gly mutation, a Ser52Pro mutation, a Gly53Glu mutation, a Gly53Ala mutation, a Glu54Gly mutation, a Glu54Lys mutation, a Glu54Leu mutation, a Leu55Arg mutation, a Leu55Pro mutation, a Leu55Gln mutation, a Leu55Glu mutation, a His56Arg mutation, a Gly57Arg mutation, a Leu58His mutation, a Leu58Arg mutation, a Thr59Lys mutation, a Thr60Ala mutation, a Glu61Lys mutation, a Glu61Gly mutation, a Phe64Leu mutation, a Phe64Ser mutation, a Gly67Glu mutation, a Ile68Leu mutation, a Tyr69His mutation, a Tyr69Ile mutation, a Lys70Asn mutation, a Val71Ala mutation, a Ile73Val mutation, a Ser77Phe mutation, a Ser77Tyr mutation, a Tyr78Phe mutation, an Ala81Val mutation, an Ala81Thr mutation, a Ile84Ser mutation, a Ile84Asn mutation, a Ile84Thr mutation, a His88Arg mutation, a Glu89Gln mutation, a Glu89Lys mutation, a His90Asp mutation, an Ala91Ser mutation, a Gln92Lys mutation, a Val94Ala mutation, an Ala97Gly mutation, an Ala97Ser mutation, an Arg103Ser mutation, a Ile107Val mutation, a Ile107Met mutation, a Ile107Phe mutation, an Ala109Ser mutation, a Leu111Met mutation, a Ser112Ile mutation, a Tyr114Cys mutation, a Tyr114His mutation, a Tyr116Ser mutation, an Ala120Ser mutation, a Val122Ile mutation, a DelVal122 mutation, a Val122Ala mutation, and an Asn124Ser mutation.

15. The antibody of any of claim 12, wherein said selective binding to said non-native TTR as compared to tetrameric TTR is evidenced by an increased amount of immunocomplexes formed between said antibody and said non-native TTR as compared to an amount of immunocomplexes formed between said antibody and said tetrameric TTR.

16. A homogenous population of monoclonal antibodies of claim 1.

17. A set of antibodies of claim 1, comprising a first antibody exhibiting selective binding to an epitope consisting essentially of amino acid residues 49-61 in SEQ ID. No. 1, and a second antibody exhibiting selective binding to an epitope consisting essentially of amino acid residues 109-121.

18. The antibody of claim 1, wherein the antibody is MFD108 produced by the hybridoma deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-120816.

19. The set of antibodies of claim 17, wherein the first antibody is MFD108 produced by the hybridoma deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-120816.