# US 9,872,920 B2 · PEGylation by the dock and lock (DNL) technique

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- Number: US 9,872,920 B2
- Document ID: US9872920B2
- Status: Granted
- Kind: B2
- Application number: 15/247,386
- Filed: 2016-08-25
- Published: 2016-12-15
- Granted: 2018-01-23
- Earliest claimed: 2005-04-06
- Assignees: IBC Pharmaceuticals, Inc.
- Applicants: IBC Pharmaceuticals, Inc.
- Inventors: Chien-Hsing Chang; David M. Goldenberg; William J. McBride; Edmund A. Rossi
- Web page: https://patentgrep.com/patent/US9872920B2

## CPC

- A61K 47/6835: {the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site}
- A61K 38/1816: {Erythropoietin [EPO]}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/212: {IFN-alpha}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/6853: {Carcino-embryonic antigens}
- A61K 51/1048: {the tumor cell determinant being a carcino embryonic antigen}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/06: Antiarrhythmics
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- B82Y 10/00: Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
- C07K 2319/00: Fusion polypeptide
- C07K 2319/70: containing domain for protein-protein interaction
- 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
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- 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)

## Abstract

The present invention concerns methods and compositions for forming PEGylated complexes of defined stoichiometry and structure. In preferred embodiments, the PEGylated complex is formed using dock-and-lock technology, by attaching a target agent to a DDD sequence and attaching a PEG moiety to an AD sequence and allowing the DDD sequence to bind to the AD sequence in a 2:1 stoichiometry, to form PEGylated complexes with two target agents and one PEG moiety. In alternative embodiments, the target agent may be attached to the AD sequence and the PEG to the DDD sequence to form PEGylated complexes with two PEG moieties and one target agent. In more preferred embodiments, the target agent may comprise any peptide or protein of physiologic or therapeutic activity. The PEGylated complexes exhibit a significantly slower rate of clearance when injected into a subject and are of use for treatment of a wide variety of diseases.

## Claims

### Claim 1

A PEGylated complex comprising:
a) a therapeutic agent attached to a DDD (dimerization and docking domain) moiety, wherein the amino acid sequence of the DDD moiety consists of the N-terminal 44 amino acids from human protein kinase A (PKA) RIIα; and
b) a PEG moiety attached to an AD (anchor domain) moiety wherein the amino acid sequence of the AD moiety is from an AKAP protein;
wherein two copies of the DDD sequences bind to one copy of the AD sequence to form a PEGylated complex.

### Claim 2 (depends on 1)

The complex of claim 1, wherein the amino acid sequence of the AD moiety is selected from the group consisting of SEQ ID NO:1.

### Claim 3 (depends on 1)

The complex of claim 1, further comprising disulfide bonds between the DDD and AD moieties.

### Claim 4 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is selected from the group consisting of an enzyme, a cytokine, a chemokine, a growth factor, an antibody and an antigen binding fragment thereof.

### Claim 5 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is selected from the group consisting of interferon-α, interferon-β, interferon-γ, MIF, HMGB-1 (high mobility group box protein 1), TNF-α, G-CSF and GM-CSF.

### Claim 6 (depends on 1)

The complex of claim 1, wherein the complex comprises a structure selected from the group consisting of: (i) IMP350: CGQIEYLAKQIVDNAIQQAGC(SS-tbu) -NH2 (SEQ ID NO:1), (ii) IMP360: CGQIEYLAKQIVDNAIQQAGC(SS-tbu)G-EDANS (SEQ ID NO:1), (iii) IMP362: PEG20-CGQIEYLAKQIVDNAIQQAGC(SS-tbu)G-EDANS (SEQ ID NO:1); and (iv) IMP413: PEG30-CGQIEYLAKQIVDNAIQQAGC(SS-tbu) G-EDANS (SEQ ID NO:1).

### Claim 7 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is a cytokine.

### Claim 8 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is interferon (IFN)-α, G-CSF or erythropoietin.

### Claim 9 (depends on 1)

The complex of claim 1, wherein the therapeutic agent attached to the DDD sequence is a fusion protein.

### Claim 10 (depends on 1)

The complex of claim 1, wherein the complex comprises one PEG moiety and two therapeutic agents.

### Claim 11 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, and IL-18.

### Claim 12 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is selected from the group consisting of Eotaxin, CCL19, CCL21, RANTES, MIP-1A, MIP-1B, ENA-78, MCP-1, IP-10, and Gro-β.

### Claim 13 (depends on 1)

The complex of claim 1, wherein the therapeutic agent is selected from the group consisting of PDGF, Flt-3 ligand, erythropoietin, thrombopoietin, hGH, CNTF, VEGF, P1GF, insulin, IGF, somatostatin, tissue plasminogen activator, and LIF.