# US 9,872,886 B2 · Compositions and methods for inhibiting cellular adhesion or directing diagnostic or therapeutic agents to RGD binding sites

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- Number: US 9,872,886 B2
- Document ID: US9872886B2
- Status: Granted
- Kind: B2
- Application number: 14/696,250
- Filed: 2015-04-24
- Published: 2016-01-28
- Granted: 2018-01-23
- Earliest claimed: 2009-11-10
- Assignees: Allegro Pharmaceuticals, LLC
- Applicants: Allegro Pharmaceuticals, Inc.
- Inventors: Michael John Mackel; John Park
- Web page: https://patentgrep.com/patent/US9872886B2

## CPC

- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 38/07: Tetrapeptides
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/1709: {from mammals}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 51/065: {conjugates with carriers being macromolecules}
- A61K 51/082: {the peptide being a RGD-containing peptide}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61L 27/227: {Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24}
- A61L 31/043: {Proteins; Polypeptides; Degradation products thereof}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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 17/08: Antiseborrheics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- 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 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 7/00: Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61L 2300/252: Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

Compounds comprising R-G-Cysteic Acid (i.e., R-G-NH—CH(CH2—SO3H)COOH or Arg-Gly-NH—CH(CH2—SO3H)COOH) and derivatives thereof, including pharmaceutically acceptable salts, hydrates, stereoisomers, multimers, cyclic forms, linear forms, drug-conjugates, pro-drugs and their derivatives. Also disclosed are methods for making and using such compounds including methods for inhibiting cellular adhesion to RGD binding sites or delivering other diagnostic or therapeutic agents to RGD binding sites in human or animal subjects.

## Claims

### Claim 1

A method of inhibiting adhesion of cells to RGD binding sites comprising administering to a subject in need thereof an effective amount of a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X1—R-G-Cysteic Acid-X
where X and X1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof.

### Claim 2 (depends on 1)

The method of claim 1 wherein the peptide is administered to the subject's eye and wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a disorder of the subject's eye.

### Claim 3 (depends on 2)

The method of claim 2 wherein the peptide is administered by intravitreal injection.

### Claim 4 (depends on 2)

The method of claim 2 wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopa thy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.

### Claim 5 (depends on 1)

The method of claim 1 wherein the peptide is administered systemically and wherein said inhibition of adhesion of cells to RGD binding sites is effective to treat a cancer which expresses an integrin that recognizes the RGD motif.

### Claim 6 (depends on 5)

The method of claim 5 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.

### Claim 7 (depends on 1)

The method of claim 1 wherein the peptide has the structural formula:

### Claim 8 (depends on 1)

The method of claim 1 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C6 alkyl, Ph or SO3H and Z is selected from H or Me; Y is selected from OH, NH2.

### Claim 9 (depends on 1)

The method of claim 1 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Proline.

### Claim 10

A method of antagonizing an RGD-binding integrin in a subject comprising administering to a subject in need thereof an effective amount of a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X1—R-G-Cysteic Acid-X
where X and X1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof.

### Claim 11 (depends on 10)

The method of claim 10 wherein the peptide is administered to the subject's eye and wherein said antagonizing of an RGD-binding integrin is effective to treat a disorder of the subject's eye.

### Claim 12 (depends on 11)

The method of claim 11 wherein the peptide is administered by intravitreal injection.

### Claim 13 (depends on 11)

The method of claim 11 wherein said antagonizing of an RGD-binding integrin is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopathy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.

### Claim 14 (depends on 10)

The method of claim 10 wherein said antagonizing of an RGD-binding integrin is effective to treat a cancer which expresses an integrin that recognizes the RGD motif.

### Claim 15 (depends on 14)

The method of claim 14 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.

### Claim 16 (depends on 10)

The method of claim 10 wherein the peptide has the structural formula:

### Claim 17 (depends on 10)

The method of claim 10 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C6 alkyl, Ph or SO3H and Z is selected from H or Me; Y is selected from OH, NH2.

### Claim 18 (depends on 10)

The method of claim 10 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Proline.

### Claim 19

A method of antagonizing an integrin in a subject comprising administering to a subject in need thereof a cyclic or linear compound comprising either:
i) a peptide which comprises Glycinyl-Arginyl-Glycinyl-Cysteic-Threonyl-Proline-COOH or
ii) a peptide which has the formula:
X1—R-G-Cysteic Acid-X
where X and X1 are selected from: Phe-Val-Ala, -Phe-Leu-Ala, -Phe-Val-Gly, -Phe-Leu-Gly, -Phe-Pro-Gly, -Phe-Pro-Ala, -Phe-Val; or from Arg, Gly, Cysteic, Phe, Val, Ala, Leu, Pro, Thr and salts thereof and any combinations of D-isomers and L-isomers thereof, wherein said integrin is one which is subject to antagonism by an RGD peptide.

### Claim 20 (depends on 19)

The method of claim 19 wherein the peptide is administered to the subject's eye and said antagonizing of an integrin is effective to treat a disorder of the subject's eye.

### Claim 21 (depends on 20)

The method of claim 20 wherein the peptide is administered by intravitreal injection.

### Claim 22 (depends on 20)

The method of claim 20 wherein the antagonizing of an integrin is effective to treat a disorder of the subject's eye selected from: neovascularization, neovascular glaucoma, diabetic retinopathy, retinal degeneration, dry macular degeneration, wet macular degeneration, corneal neovascularization and vitreo-macular traction.

### Claim 23 (depends on 19)

The method of claim 19 wherein the peptide is administered systemically to treat a cancer which expresses an integrin that recognizes the RGD motif.

### Claim 24 (depends on 23)

The method of claim 23 wherein the cancer comprises a vascularized solid tumor or metastatic lesions from a vascularized solid tumor.

### Claim 25 (depends on 19)

The method of claim 19 wherein the peptide has the structural formula:

### Claim 26 (depends on 19)

The method of claim 19 wherein the peptide has the structural formula:
where X′ is selected from: H, C1-C6 alkyl, Ph or SO3H and Z is selected from H or Me; Y is selected from OH or NH2.

### Claim 27 (depends on 19)

The method of claim 19 wherein the peptide comprises Glycine-Arginine-Glycine-Cysteic (Acid)-Threonine-Pro.