Methods and compositions for increasing α-L-iduronidase activity in the CNS

• US 9,567,400 B2
• Filed: 01/27/2015
• Issued: 02/14/2017
• Est. Priority Date: 07/27/2007
• Status: Active Grant

• Current Assignee: JCR Pharmaceuticals Co., Ltd.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Pardridge, William M., Boado, Ruben J.
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US14/606,239
• Publication Number:
  US 20150299328A1
• Time in Patent Office: 749 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6801 Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/6815 Enzymes
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 16/46 Hybrid immunoglobulins hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• 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 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C12N 9/0002 : Antibodies with enzymatic activity, e.g. abzymes
• CPC Class Codes: C12N 9/2402 : hydrolysing O- and S- glycosyl compounds (3.2.1)
• CPC Class Codes: C12Y 302/01076 : L-Iduronidase (3.2.1.76)

Abstract

Provided herein are methods and compositions for treating a subject suffering from a deficiency in α-L-Iduronidase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a human insulin receptor and an α-L-Iduronidase. A therapeutically effective systemic dose is based on the specific CNS uptake characteristics of human insulin receptor antibody-α-L-Iduronidase fusion antibodies as described herein.

Claims

1. A method of treating a central nervous system α

-L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α

-L-iduronidase activity, wherein;

(a) at least about 25,000 units of α

-L-iduronidase activity are delivered to a brain tissue of the subject in need thereof;

(b) the therapeutically effective dose of a fusion antibody having α

-L-iduronidase activity comprises at least about 200,000 units of α

-L-iduronidase activity/Kg of body weight;

(c) the fusion antibody having α

-L-iduronidase activity comprises a fusion protein comprising an amino acid sequence of an immunoglobulin heavy chain and an α

-L-iduronidase;

(d) the fusion antibody having α

-L-iduronidase activity binds to an endogenous receptor of a blood brain barrier (BBB) transport system; and

(e) the amino acid sequence of the α

-L-iduronidase is covalently linked at its amino terminus to the carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain,

wherein the α

-L-iduronidase retains at least 30% of its enzymatic activity compared to an unfused α

-L-iduronidase.

2. The method of claim 1, wherein the endogenous receptor of a blood brain barrier (BBB) transport system is an insulin receptor, transferrin receptor, IGF receptor, or leptin receptor.

3. The method of claim 1, wherein the endogenous receptor of a blood brain barrier (BBB) transport system is an insulin receptor.

4. The method of claim 1, wherein the endogenous receptor of a blood brain barrier (BBB) transport system is a human insulin receptor.

5. The method of claim 1, wherein the subject is a human subject.

6. The method of claim 1, wherein the IDUA specific activity of the fusion antibody is at least 200,000 units/mg.

7. The method of claim 1, wherein the systemic administration is parenteral, intravenous, subcutaneous, intramuscular, trans-nasal, intra-arterial, transdermal, or respiratory.

8. The method of claim 1, wherein the systemic administration is intravenous.

9. The method of claim 1, wherein the delivery occurs within two hours or less after systemic administration.

10. The method of claim 1, wherein the fusion protein is at least 95% identical to SEQ ID NO:

10.

11. The method of claim 1, wherein the fusion protein comprises SEQ ID NO:

10.

12. The method of claim 1, wherein the α

-L-iduronidase retains at least 40% of its enzymatic activity compared to an unfused α

-L-iduronidase.

13. The method of claim 1, wherein the therapeutically effective dose comprises at least about 300,000 units of α

-L-iduronidase activity/Kg of body weight.

14. The method of claim 1, wherein the fusion antibody having α

-L-iduronidase activity is a single chain antibody.

15. The method of claim 1, wherein the fusion antibody having α

-L-iduronidase activity is a single chain Fv (scFv) antibody.

16. The method of claim 1, wherein the fusion antibody having α

-L-iduronidase activity is a monoclonal antibody.

17. The method of claim 1, wherein the fusion antibody having α

-L-iduronidase activity further comprises an immunoglobulin light chain.

18. The method of claim 1, wherein the fusion antibody further comprises a Fab region that binds to an endogenous receptor of a brain cell membrane (BCM) transport system.

19. The method of claim 1, wherein the therapeutically effective dose has no detectable aggregates.

20. The method of claim 1, wherein the therapeutically effective dose comprises polysorbate.

21. The method of claim 1, wherein the therapeutically effective dose comprises polysorbate at a concentration of 0.01-1%.

22. The method of claim 1, wherein the therapeutically effective dose comprises polysorbate-80.

23. The method of claim 1, wherein the therapeutically effective dose comprises polysorbate-80 at a concentration of 0.01-1%.

24. The method of claim 1, wherein the fusion protein having α

-L-iduronidase activity catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in dermatan sulfate.

25. The method of claim 1, wherein the fusion protein having α

-L-iduronidase activity catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in heparan sulfate.

26. A method for treating a central nervous system α

-L-iduronidase deficiency in a subject in need thereof, comprising systemically administering to the subject in need thereof a therapeutically effective dose of a fusion antibody having α

-L-iduronidase activity, wherein;

(a) at least about 25,000 units of α

-L-iduronidase activity are delivered to a brain tissue of the subject in need thereof wherein the therapeutically effective dose comprises at least about 200,000 units of α

-L-iduronidase activity/Kg of body weight;

(b) the fusion antibody having α

-L-iduronidase activity comprises;

(a) a fusion protein comprising the amino acid sequence of an immunoglobulin light chain that comprises a variable region and a constant region and an α

-L-iduronidase;

(c) the fusion antibody having α

-L-iduronidase activity binds to an endogenous receptor of a blood brain barrier (BBB) transport system and catalyzes hydrolysis of unsulfated alpha-L-iduronosidic linkages in at least one of dermatan sulfate and heparan sulfate; and

(d) the amino acid sequence of the α

-L-iduronidase is covalently linked at its amino terminus to the carboxy terminus of the amino acid sequence of the immunoglobulin light chain,

wherein the α

-L-iduronidase retains at least 30% of its enzymatic activity compared to an unfused α

-L-iduronidase.

27. The method of claim 26, wherein the fusion antibody further comprises an immunoglobulin heavy chain.

28. The method of claim 26, wherein the therapeutically effective dose comprises polysorbate.

29. The method of claim 26, wherein the therapeutically effective dose comprises polysorbate at a concentration of 0.01-1%.

30. The method of claim 26, wherein the therapeutically effective dose comprises polysorbate-80.

31. The method of claim 26, wherein the therapeutically effective dose comprises polysorbate-80 at a concentration of 0.01-1%.