COMPOSITIONS AND METHODS FOR BLOOD-BRAIN BARRIER DELIVERY OF ORGANOPHOSPHATASES

• US 20100098693A1
• Filed: 10/06/2009
• Published: 04/22/2010
• Est. Priority Date: 10/07/2008
• Status: Abandoned Application

• Current Assignee: ArmaGen Technologies, Inc.
• Original Assignee: ArmaGen Technologies, Inc.
• Inventors: Boado, Ruben J., Pardridge, William M.
• Application Number:
  US12/574,571
• Publication Number:
  US 20100098693A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: C12N 9/18 Carboxylic ester hydrolases (3.1.1)

Abstract

Provided herein are compositions and related methods for delivering an organophosphatase to the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody to a receptor expressed on the surface of the blood-brain barrier (BBB receptor) and an organophosphatase. In some embodiments, the compositions described herein are used to treat a subject suffering from or at high risk of exposure to an organophosphate (e.g., a nerve gas).

Claims

1. A method for treating organophosphate intoxication in a subject in need thereof, comprising systemically administering to the subject a dose of a fusion antibody having organophosphatase activity and binding to the extracellular domain of a receptor expressed on the BBB.

2. The method of claim 1, wherein the receptor is an insulin receptor, a transferrin receptor, or a lipoprotein receptor.

3. The method of claim 2, wherein the fusion antibody binds to an extracellular domain of the human insulin receptor.

4. The method of claim 1, wherein at least about 0.5% of the systemically administered dose is delivered to the brain.

5. The method of claim 1, wherein the fusion antibody comprises an amino acid sequence at least 70% identical to the amino acid sequence of human PON1.

6. The method of claim 1, wherein the subject is suffering from acute exposure to an organophosphate.

7. The method of claim 1, wherein the subject is suffering from chronic exposure to an organophosphate.

8. The method of claim 1, wherein the fusion antibody comprises an immunoglobulin heavy chain comprising a CDR1 corresponding to the amino acids 45-54 of SEQ ID NO:

21 with up to 4 single amino acid mutations, a CDR2 corresponding to the amino acids 69-85 of SEQ ID NO;

21 with up to 6 single amino acid mutations, or a CDR3 corresponding to the amino acids 118-121 of SEQ ID NO;

21 with up to 3 single amino acid mutations, wherein the single amino acid mutations are substitutions, deletions, or insertions.

9. The method of claim 1, wherein the fusion antibody comprises an immunoglobulin heavy chain comprising a CDR1 corresponding to the amino acids 45-54 of SEQ ID NO:

21 with up to 4 single amino acid mutations, a CDR2 corresponding to the amino acids 69-85 of SEQ ID NO;

21 with up to 6 single amino acid mutations, or a CDR3 corresponding to the amino acids 118-121 of SEQ ID NO;

21 with up to 5 single amino acid mutations, wherein the single amino acid mutations are substitutions, deletions, or insertions.

10. A method for protecting a subject from organophosphate intoxication comprising systemically administering to a subject at high risk of organophosphate intoxication a dose of a fusion antibody having organophosphatase activity and binding to the extracellular domain of a receptor expressed on the BBB.

11. The method of claim 10, wherein the receptor is an insulin receptor, a transferrin receptor, or a lipoprotein receptor.

12. The method of claim 10, wherein at least about 0.5% of the systemically administered dose is delivered to the brain.

13. The method of claim 10, wherein the fusion antibody comprises an amino acid sequence at least 70% identical to the amino acid sequence of human PON1.

14. The method of claim 10, wherein the fusion antibody binds to an extracellular domain of the human insulin receptor

15. A method for treating of cerebral atherosclerosis, comprising administering to a subject in need thereof a dose of a fusion antibody that has organophosphatase activity and binds to the extracellular domain of a receptor expressed on the BBB.

16. A fusion antibody comprising a heavy chain immunoglobulin or a light chain immunoglobulin covalently linked to an organophosphatase, wherein the fusion antibody binds to the extracellular domain of a receptor expressed on the BBB.

17. The fusion antibody of claim 16, wherein the receptor is an insulin receptor, a transferrin receptor, or a lipoprotein receptor

18. The fusion antibody of claim 16, wherein the fusion antibody binds to an extracellular domain of the human insulin receptor

19. The fusion antibody of claim 16, wherein the fusion antibody comprises an immunoglobulin heavy chain comprising a CDR1 corresponding to the amino acid s 45-54 of SEQ ID NO:

21 with up to 4 single amino acid mutations, a CDR2 corresponding to the amino acids 69-85 of SEQ ID NO;

21 with up to 6 single amino acid mutations, or a CDR3 corresponding to the amino acids 118-121 of SEQ ID NO;

21 with up to 3 single amino acid mutations, wherein the single amino acid mutations are substitutions, deletions, or insertions.

20. The fusion antibody of claim 19, wherein the fusion antibody comprises an immunoglobulin heavy chain comprising a CDR1 corresponding to the amino acids 45-54 of SEQ ID NO:

21 with up to 4 single amino acid mutations, a CDR2 corresponding to the amino acids 69-85 of SEQ ID NO;

21 with up to 6 single amino acid mutations, or a CDR3 corresponding to the amino acids 118-121 of SEQ ID NO;

21 with up to 5 single amino acid mutations, wherein the single amino acid mutations are substitutions, deletions, or insertions.

21. The fusion antibody of claim 16, wherein the immunoglobulin light chain comprises a CDR1 corresponding to the amino acids 45-54 of SEQ ID NO:

21 with up to 4 single amino acid mutations, a CDR2 corresponding to the amino acids 69-85 of SEQ ID NO;

21 with up to 6 single amino acid mutations, or a CDR3 corresponding to the amino acids 118-121 of SEQ ID NO;

21 with up to 5 single amino acid mutations, wherein the single amino acid mutations are substitutions, deletions, or insertions.

22. The fusion antibody of claim 16, wherein the fusion antibody competes for binding to the human insulin receptor with an antibody comprising a heavy chain comprising amino acids 20-462 of SEQ ID NO 21.