# US 12,760,068 B2 · Optimized peptides for targeting human nerves and their use in image guided surgery, diagnostics and therapeutic delivery

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- Number: US 12,760,068 B2
- Document ID: US12760068B2
- Status: Granted
- Kind: B2
- Application number: 18/458,690
- Filed: 2023-08-30
- Published: 2024-04-18
- Granted: 2026-10-13
- Earliest claimed: 2017-08-02
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Quyen T. Nguyen; Mike Whitney; Dina Hingorani; Roger Y. Tsien; Stephen Adams
- Web page: https://patentgrep.com/patent/US12760068B2

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- 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 41/0057: {Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent}
- 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 49/0056: {Peptides, proteins, polyamino acids}
- C07K 7/00: Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- G01N 33/5005: {involving human or animal cells (immunoassay G01N33/56966; immunoassays of protozoa G01N33/56905; protozoa in screening assays C12Q1/025)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention provides methods for guiding preservation of human neurons or human nerves during surgery by administering a fluorescently-labeled peptide that specifically binds to the human neurons or human nerves. The invention further provides human neuron or nerve targeting molecules comprising fluorescently-labeled peptides that specifically bind to human neurons or human nerves and compositions thereof.

## Claims

### Claim 1

A targeting molecule comprising a peptide having the sequence set forth in SGQVPWEEPYYVVKKSS (HNP-401, SEQ ID NO:1) or a variant thereof having 2-8 amino acids deleted from the N-terminus or C-terminus, wherein the peptide is conjugated to a drug.

### Claim 2 (depends on 1)

The targeting molecule of claim 1, wherein the peptide has the sequence set forth in SGQVPWEEPYYVVKKSS (HNP-401, SEQ ID NO:1); QVPWEEPYYVVKKSS (HNP401-N-2; SEQ ID NO:20); PWEEPYYVVKKSS (HNP401-N-4; SEQ ID NO:22); EEPYYVVKKSS (HNP401-N-6; SEQ ID NO:23); PYYVVKKSS (HNP401-N-8; SEQ ID NO: 24); SGQVPWEEPYYVVKK (HNP401-C-2; SEQ ID NO:25); SGQVPWEEPYYVV (HNP401-C-4; SEQ ID NO:26); SGQVPWEEPYY (HNP401-C-6; SEQ ID NO:27); or SGQVPWEEP (HNP401-C-8; SEQ ID NO:28).

### Claim 3 (depends on 1)

The targeting molecule of claim 1, wherein the drug is directly attached to the peptide.

### Claim 4 (depends on 1)

The targeting molecule of claim 1, wherein the peptide further comprises a linker.

### Claim 5 (depends on 4)

The targeting molecule of claim 4, wherein the linker is a straight or branched-chain carbon linker, heterocyclic carbon linker, amino acid linker, lipophilic residue, peptide linker, peptide nucleic acid linker, hydrazone linker, SPDB disulfide, sulfo-SPDB, maleimidomethyl cyclohexane-1-carboxylate (MCC), aminohexanoic acid linker, polyether linker, or polyethylene glycol linker.

### Claim 6 (depends on 1)

The targeting molecule of claim 1, wherein the peptide further comprises GC, GG, or GGC residues at the C-terminus of the peptide.

### Claim 7 (depends on 6)

The targeting molecule of claim 6, wherein the peptide has the sequence selected from the group consisting of Ac-SGQVPWEEPYYVVKKSSGGC (HNP401 with GGC linker; SEQ ID NO:4), Ac-QVPWEEPYYVVKKSSGGC (HNP401-N-2 with GGC linker; SEQ ID NO: 7), Ac-PWEEPYYVVKKSSGGC (HNP401-N-4 with GGC linker; SEQ ID NO:8), Ac-EEPYYVVKKSSGGC (HNP401-N-6 with GGC linker; SEQ ID NO:9), Ac-PYYVVKKSSGGC (HNP401-N-8 with GGC linker; SEQ ID NO:10), Ac-SGQVPWEEPYYVVKKGGC (HNP401-C-2 with GGC linker; SEQ ID NO:11), Ac-SGQVPWEEPYYVVGGC (HNP401-C-4 with GGC linker; SEQ ID NO:12), Ac-SGQVPWEEPYYGGC (HNP401-C-6 with GGC linker; SEQ ID NO: 13), Ac-SGQVPWEEPGGC (HNP401-C-8 with GGC linker; SEQ ID NO:14), QVPWEEPYYVVKKSSGG (HNP401-N-2 with GG linker; SEQ ID NO:21), PWEEPYYVVKKSSGG (HNP401-N-4 with GG linker; SEQ ID NO:118), EEPYYVVKKSSGG (HNP401-N-6 with GG linker; SEQ ID NO:119), PYYVVKKSSGG (HNP401-N-8 with GG linker; SEQ ID NO:120), SGQVPWEEPYYVVKKGG (HNP401-C-2; with GG linker; SEQ ID NO:121), SGQVPWEEPYYVVGG (HNP401-C-4 with GG linker; SEQ ID NO:122), SGQVPWEEPYYGG, (HNP401-C-6 with GG linker; SEQ ID NO:123), and SGQVPWEEPGG (HNP401-C-8 with GG linker; SEQ ID NO:124).

### Claim 8 (depends on 3)

The targeting molecule of claim 3, wherein the drug is conjugated to the N-terminus or C-terminus of the peptide.

### Claim 9 (depends on 4)

The targeting molecule of claim 4, wherein the drug is conjugated to the N-terminus or C-terminus of the peptide.

### Claim 10 (depends on 7)

The targeting molecule of claim 7, wherein the drug is conjugated to the N-terminus or C-terminus of the peptide.

### Claim 11 (depends on 1)

The targeting molecule of claim 1, wherein the drug is selected from the group consisting of: an antihistamine, a GABA receptor modulator, a neurotransmitter reuptake inhibitor, a local anesthetic, an anticholinergic, a sodium channel blocker, a calcium channel blocker, a thyrotropin-releasing hormone, a y-secretase inhibitor, an AMPA receptor agonist or antagonist, an NMDA receptor agonist or antagonist, an mGlu receptor agonist or antagonist, a growth factor, an antiemetic agent, a corticosteroid; a cytotoxic agent; an antioxidant, an iron chelator, a mitochondrial modulator, a sirtuin modulator, a nitric oxide (NO) and/or nitric oxide synthase (NOS) modulator, a potassium channel agonist or antagonist, a purinergenic receptor agonist or antagonist, and any combination thereof.

### Claim 12 (depends on 1)

The targeting molecule of claim 1, wherein the drug is an anesthetic or pain reliever.

### Claim 13 (depends on 12)

The targeting molecule of claim 12, wherein the anesthetic or pain reliever is selected from the group consisting of: benzocaine; carticaine; cinchocaine; cyclomethycaine; lidocaine; prilocaine; propxycaine; proparacaine; tetracaine; tocainide; and trimecaine.

### Claim 14 (depends on 1)

The targeting molecule of claim 1, wherein the drug is a cytotoxic agent.

### Claim 15 (depends on 1)

The targeting molecule of claim 1, wherein the cytotoxic agent is selected from the group consisting of methotrexate; cyclophosphamide; thalidomide; paclitaxel; pemetrexed; pentostatin; pipobroman; pixantrone; plicamycin; platonin; procarbazine; raltitrexed; rebeccamycin; rubitecan; SN-38; salinosporamide A; satraplatin; streptozotocin; swainsonine; tariquidar; taxane; tegafur-uracil; temozolomide; testolactone; thioTEPA; tioguanine; topotecan; trabectedin; tretinoin; triplatin tetranitrate; tris(2-chloroethyl)amine; troxacitabine; uracil mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; and zosuquidar.

### Claim 16 (depends on 1)

The targeting molecule of claim 1, wherein the drug reduces undesired neuron or nerve impulses.

### Claim 17 (depends on 16)

The targeting molecule of claim 16, wherein the drug that reduces undesired neuron or nerve impulses is selected from the group consisting of carbamazepine; oxcarbazepine; phenytein; valproic acid; sodium valproate; cinnarizine; flunarizine; and nimodipine.

### Claim 18 (depends on 1)

The targeting molecule of claim 1, wherein the drug is a growth factor.

### Claim 19 (depends on 18)

The targeting molecule of claim 18, wherein the growth factor is selected from the group consisting of brain-derived neurotrophic factor (BDNF); ciliary neurotrophic factor (CNTF); glial cell-line derived neurotrophic factor (GDNF); neurotrophin-3; neurotrophin-4; fibroblast growth factor (FGF) receptor; insulin-like growth factor (IGF); and any combination thereof.

### Claim 20 (depends on 1)

A method of delivering a drug to a human neuron or nerve comprising contacting the human neuron or nerve with a targeting molecule of claim 1.

### Claim 21 (depends on 20)

The method of claim 20, wherein the targeting molecule is administered to a human subject.

### Claim 22 (depends on 21)

The method of claim 21, wherein the targeting molecule is administered systemically to the human subject.

### Claim 23 (depends on 21)

The method of claim 21, wherein the targeting molecule is administered locally to the human subject.

### Claim 24 (depends on 21)

The method of claim 21, wherein the targeting molecule is administered parenterally to the human subject.

### Claim 25 (depends on 24)

The method of claim 24, wherein the targeting molecule is administered intravenously to the human subject.