# US 8,080,518 B2 · Co-administration of an agent linked to an internalization peptide with an anti-inflammatory

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- Number: US 8,080,518 B2
- Document ID: US8080518B2
- Status: Granted
- Kind: B2
- Application number: 12/323,915
- Filed: 2008-11-26
- Published: 2009-07-09
- Granted: 2011-12-20
- Earliest claimed: 2007-12-05
- Assignees: Arbor Vita Corporation; NoNO Inc.
- Inventors: Michael Tymianski; Jonathan David Garman
- Web page: https://patentgrep.com/patent/US8080518B2

## CPC

- A61K 38/1787: {for neuromediators, e.g. serotonin receptor, dopamine receptor}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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

The invention provides methods of delivering pharmacologic agents linked to an internalization peptide, in which an inflammatory response inducible by the internalization peptide is inhibited by co-administration of an anti-inflammatory or by linking the internalization peptide to biotin or similar molecule. Such methods are premised in part on the results described in the examples whereby administration of a pharmacological agent linked to tat high dosages is closely followed by an inflammatory response, which includes mast cell degranulation, histamine release and the typical sequelae of histamine release, such as redness, heat, swelling, and hypotension.

## Claims

### Claim 1

A method of delivering a pharmacologic agent to a subject, the method comprising:
administering the pharmacologic agent linked to an internalization peptide to the subject; and
administering an anti-inflammatory agent to the subject, whereby the anti-inflammatory agent inhibits an inflammatory response from mast cell degranulation induced by the internalization peptide; wherein the pharmacological agent is a peptide having an amino acid sequence comprising ESDV (SEQ ID NO:12) or ETDV (SEQ ID NO:40) and the internalization peptide has an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51).

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-inflammatory agent is an anti-histamine.

### Claim 3 (depends on 1)

The method of claim 1, wherein the anti-inflammatory agent is a corticosteroid.

### Claim 4 (depends on 1)

The method of claim 1, wherein the internalization peptide is a tat peptide having an amino acid sequence comprising GRKKRRQRRR (SEQ ID NO:1).

### Claim 5 (depends on 1)

The method of claim 1 wherein the internalization peptide is a tat peptide having an amino acid sequence comprising YGRKKRRQRRR (SEQ ID NO:2).

### Claim 6 (depends on 1)

The method of claim 1, wherein the internalization peptide is a tat peptide having an amino acid sequence comprising GRKKRRQRRRP (SEQ ID NO: 69).

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmacologic agent is KLSSIESDV (SEQ ID NO:5).

### Claim 8

A method of treating or effecting prophylaxis of a disease characterized by excitotoxicity comprising
administering to a subject having or at risk of the disease a pharmacologic agent that inhibits binding of PSD95 to NDMAR 2B linked to an internalization peptide in a regime effective to treat or effect prophylaxis of the disease; and
administering to the subject an anti-inflammatory agent, whereby the anti-inflammatory agent inhibits an inflammatory response from mast cell degranulation induced by the internalization peptide
wherein the pharmacological agent is a peptide having an amino acid sequence comprising ESDV (SEQ ID NO:12) or ETDV (SEQ ID NO:40) and the internalization peptide has an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51).

### Claim 9 (depends on 8)

The method of claim 8, wherein the internalization peptide is a tat peptide having an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51), GRKKRRQRRR (SEQ ID NO:1), YGRKKRRQRRR (SEQ ID NO:2), FGRKKRRQRRR (SEQ ID NO:3) or GRKKRRQRRRPQ (SEQ ID NO:4).

### Claim 10 (depends on 8)

The method of claim 8, wherein the subject is female.

### Claim 11 (depends on 8)

The method of claim 8, wherein the disease is stroke or traumatic injury to the CNS not involving stroke.

### Claim 12 (depends on 8)

The method of claim 8, wherein the subject is at risk of transient cerebral ischemic attack or stroke as a result of undergoing heart surgery.

### Claim 13

In a method of delivering a pharmacologic agent linked to an internalization peptide to a subject, the improvement wherein the internalization peptide is administered with a mast cell degranulation inhibitor to inhibit mast cell degranulation inducible by the internalization peptide, wherein the pharmacological agent is a peptide having an amino acid sequence comprising ESDV (SEQ ID NO:12) or ETDV (SEQ ID NO:40) and the internalization peptide has an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51).

### Claim 14

A method of delivering a pharmacologic agent to a subject the method comprising:
administering the pharmacologic agent linked to an internalization peptide to a subject, wherein the subject has been or will be administered a mast cell degranulation inhibitor within a time window starting six hours before and ending one hour after the pharmacologic agent is administered) to inhibit mast cell degranulation inducible by the internalization peptide, wherein the pharmacological agent is a peptide having an amino acid sequence comprising ESDV (SEQ ID NO:12) or ETDV (SEQ ID NO:40) and the internalization peptide has an amino acid sequence comprising RKKRRQRRR (SEQ ID NO:51.

### Claim 15 (depends on 1)

The method of claim 1, wherein the anti-inflammatory agent is a mast cell degranulation inhibitor.

### Claim 16 (depends on 8)

The method of claim 8, wherein the anti-inflammatory agent is a mast cell degranulation inhibitor.

### Claim 17 (depends on 13)

The method of claim 13, wherein the mast cell degranulation inhibitor is administered within a time window starting six hours before and ending one hour after the pharmacologic agent is administered.

### Claim 18 (depends on 1)

The method of claim 1, wherein the anti-inflammatory agent is administered intravenously.

### Claim 19 (depends on 8)

The method of claim 8, wherein the mast cell degranulation inhibitor is administered intravenously.

### Claim 20 (depends on 14)

The method of claim 14, wherein the mast cell degranulation inhibitor is administered intravenously.