# US 11,028,156 B2 · Methods and compositions for increasing iduronate 2-sulfatase activity in the CNS

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- Number: US 11,028,156 B2
- Document ID: US11028156B2
- Status: Granted
- Kind: B2
- Application number: 15/982,990
- Filed: 2018-05-17
- Published: 2018-09-06
- Granted: 2021-06-08
- Earliest claimed: 2009-10-09
- Assignees: Armagen, Inc.
- Applicants: Armagen, Inc.
- Inventors: William M. Pardridge; Ruben J. Boado
- Web page: https://patentgrep.com/patent/US11028156B2

## CPC

- C07K 16/18: against material from animals or humans
- 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
- C07K 16/2869: {against hormone receptors (for antibodies against neuromediator receptors C07K16/286)}
- C12N 9/16: acting on ester bonds (3.1)
- 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)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C12Y 301/06013: Iduronate-2-sulfatase (3.1.6.13)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12Y: ENZYMES

## Abstract

Provided herein are methods and compositions for treating a subject suffering from a deficiency in iduronate 2-sulfatase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody that crosses the blood brain barrier (BBB) and an iduronate 2-sulfatase.

## Claims

### Claim 1

A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter's syndrome, comprising systemically administering to the subject with Hunter's syndrome a therapeutically effective dose of a fusion antibody comprising:
(a) an immunoglobulin that crosses a blood brain barrier (BBB), wherein the immunoglobulin comprises an immunoglobulin heavy chain; and
(b) an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to the amino terminus of the amino acid sequence of the immunoglobulin heavy chain, thereby forming a fusion protein;
wherein the fusion antibody crosses the blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of the L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin, wherein the iduronate-2-sulfatase retains at least 20% of its activity compared to its activity as a separate entity after crossing a BBB of the subject with Hunter's syndrome and entering a lysosomal compartment of a cell in a central nervous system of the subject with Hunter's syndrome, and wherein the iduronate-2-sulfatase specific activity of the fusion antibody is at least 10,000 units/mg.

### Claim 2 (depends on 1)

The method of claim 1, wherein the fusion antibody further comprises an immunoglobulin light chain.

### Claim 3 (depends on 1)

The method of claim 1, wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1).

### Claim 4 (depends on 1)

The method of claim 1, wherein the fusion antibody reduces glycosoaminoglycan (GAG) accumulation in Hunter fibroblasts when administered to a medium comprising said Hunter fibroblasts.

### Claim 5 (depends on 1)

The method of claim 1, wherein the immunoglobulin retains at least 20% of its activity compared to its activity as a separate entity.

### Claim 6 (depends on 1)

The method of claim 1, wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG.

### Claim 7 (depends on 2)

The method of claim 2, wherein the immunoglobulin light chain is an immunoglobulin light chain of lambda class.

### Claim 8 (depends on 2)

The method of claim 2, wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class.

### Claim 9 (depends on 1)

The method of claim 1, wherein the fusion antibody crosses the BBB by binding to an endogenous BBB receptor-mediated transport system.

### Claim 10 (depends on 1)

The method of claim 1, wherein the fusion antibody crosses the BBB via an endogenous BBB receptor selected from the group consisting of an insulin receptor, a transferrin receptor, a leptin receptor, a lipoprotein receptor, and an IGF receptor.

### Claim 11 (depends on 1)

The method of claim 1, wherein the fusion antibody crosses the BBB by binding an insulin receptor.

### Claim 12 (depends on 1)

The method of claim 1, wherein the iduronate-2-sulfatase is at least 90% identical to SEQ ID NO:9.

### Claim 13 (depends on 1)

The method of claim 1, wherein the fusion antibody comprises a formylglycine.

### Claim 14 (depends on 1)

The method of claim 1, wherein the fusion protein further comprises a linker between the amino acid sequence of the iduronate-2-sulfatase and the amino terminus of the amino acid sequence of the immunoglobulin heavy chain.