# US 8,569,231 B2 · Soluble non-depot insulin conjugates and uses thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,569,231 B2
- Document ID: US8569231B2
- Status: Granted
- Kind: B2
- Application number: 13/257,507
- Filed: 2010-01-27
- Published: 2012-01-12
- Granted: 2013-10-29
- Earliest claimed: 2009-03-20
- Assignees: SmartCells, Inc.
- Applicants: Todd C. Zion; Thomas M. Lancaster
- Inventors: Todd C. Zion; Thomas M. Lancaster
- Web page: https://patentgrep.com/patent/US8569231B2

## CPC

- C07K 14/62: Insulins
- A61K 38/28: Insulins
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/6415: {Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins}
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07K 14/4713: {Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens}
- C07K 14/4743: {Insulin-like growth factor binding protein}
- C07K 14/65: Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
- 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)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In one aspect, the disclosure provides a conjugate comprising an insulin molecule having an A-chain and a B-chain; an affinity ligand covalently bound to the A-chain; and a monovalent glucose binding agent covalently bound to the B-chain, wherein the affinity ligand competes with glucose for non-covalent binding with the monovalent glucose binding agent. In the absence of glucose, the monovalent glucose binding agent binds the affinity ligand to produce a “closed” inactive form of the insulin molecule. When free glucose is added, it competes with the affinity ligand for binding with the monovalent glucose binding agent to produce an “open” active form of the insulin molecule. The monovalent glucose binding agent and affinity ligand are covalently bound to the insulin molecule. The disclosure also provides methods of using these conjugates and methods of making these conjugates. In another aspect, the disclosure provides exemplary conjugates. The disclosure also provides alternative conjugates that are not necessarily activated by glucose.

## Claims

### Claim 1

A conjugate comprising:
an insulin molecule having an A-chain and a B-chain;
an affinity ligand covalently bound to the A-chain; and
a monovalent glucose binding agent covalently bound to the B-chain, wherein the monovalent glucose binding agent is a polynucleotide aptamer comprising the nucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and wherein the affinity ligand competes with glucose for non-covalent binding with the monovalent glucose binding agent.

### Claim 2 (depends on 1)

The conjugate of claim 1, wherein in the absence of glucose, the monovalent glucose binding agent binds the affinity ligand to produce an inactive form of insulin.

### Claim 3 (depends on 1)

The conjugate of claim 1, wherein in the presence of excess glucose, glucose competes with the affinity ligand for binding with the monovalent glucose binding agent to produce an active form of insulin.

### Claim 4 (depends on 1)

The conjugate of claim 1, wherein the affinity ligand includes a saccharide selected from the group consisting of glucose, mannose, glucosamine, mannosamine, methylglucose, methylmannose, ethylglucose, and ethylmannose.

### Claim 5 (depends on 1)

The conjugate of claim 1, wherein the monovalent glucose binding agent is chemically modified.

### Claim 6 (depends on 1)

The conjugate of claim 1, wherein the monovalent glucose binding agent is pegylated.

### Claim 7 (depends on 1)

A method comprising administering a conjugate of claim 1 to a patient in need thereof.

### Claim 8 (depends on 7)

The method of claim 7, wherein the patient is diabetic.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

A kit comprising a pharmaceutical composition of claim 9 and a syringe or pen.

### Claim 11 (depends on 10)

The kit of claim 10, wherein the pharmaceutical composition is in a container separate from the syringe or pen.

### Claim 12 (depends on 11)

The kit of claim 11, wherein the pharmaceutical composition comprises a non-liquid carrier and the kit further comprises a liquid carrier in a container separate from the syringe or pen.