PEPTIDE REAGENTS AND METHODS FOR DETECTION AND TARGETING OF DYSPLASIA, EARLY CANCER AND CANCER

• US 20170246324A1
• Filed: 08/21/2015
• Published: 08/31/2017
• Est. Priority Date: 08/22/2014
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Wang, Thomas D., Zhou, Juan, Joshi, Bishnu P.
• Granted Patent: US 10,500,290 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: C07K 14/485 Epidermal growth factor [EGF], i.e. urogastrone
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/57419 of colon

Abstract

The present invention is directed to EGFR-specific peptide reagents, methods for detecting pre-cancer, early cancer and/or cancer using the peptide reagents, and methods for targeting pre-cancer cells, early cancer cells and/or cancer cells using the peptide reagents. In one aspect, the disclosure provides reagents consisting essentially of a peptide QRHKPRE (SEQ ID NO: 1), HAHRSWS (SEQ ID NO: 2), YLTMPTP (SEQ ID NO: 3), TYPISFM (SEQ ID NO: 4), KLPGWSG (SEQ ID NO: 5), IQSPHFF (SEQ ID NO: 6), YSIPKSS (SEQ ID NO: 7), SHRNRPRNTQPS (SEQ ID NO: 8), NRHKPREKTFTD (SEQ ID NO: 9).

Claims

1. A reagent consisting essentially of a peptide QRHKPRE (SEQ ID NO:

1), HAHRSWS (SEQ ID NO;

     2), YLTMPTP (SEQ ID NO;

     3), TYPISFM (SEQ ID NO;

     4), KLPGWSG (SEQ ID NO;

     5), IQSPHFF (SEQ ID NO;

     6), YSIPKSS (SEQ ID NO;

     7), SHRNRPRNTQPS (SEQ ID NO;

     8), NRHKPREKTFTD (SEQ ID NO;

     9), TAVPLKRSSVTI (SEQ ID NO;

     10), GHTANRQPWPND (SEQ ID NO;

     11), LSLTRTRHRNTR (SEQ ID NO;

     12), RHRDTQNHRPTN (SEQ ID NO;

     13), ARHRPKLPYTHT (SEQ ID NO;

     14), KRPRTRNKDERR (SEQ ID NO;

     15), SPMPQLSTLLTR (SEQ ID NO;

     16) or NHVHRMHATPAY (SEQ ID NO;

     17).

or a multimer form of the peptide, wherein the peptide specifically binds to epidermal growth factor receptor.

2. The reagent of claim 1 comprising a detectable label attached to the peptide.

3. The reagent of claim 2 wherein the detectable label is detectable by microscopy, photoacoustic, PET, SPECT, ultrasound or magnetic resonance imaging.

4. The reagent of claim 3 wherein the label detectable by microscopy is fluorescein isothiocyanate (FITC).

5. The reagent of claim 3 wherein the label detectable by microscopy is Cy5.

6. The reagent of claim 3 wherein the label detectable by microscopy is Cy5.5.

7. The reagent of claim 3 wherein the label detectable by microscopy is IRdye800.

8. The reagent of claim 1 wherein the multimer form of the peptide is a dimer.

9. The reagent of claim 2 wherein the detectable label is attached to the peptide by a peptide linker.

10. The reagent of claim 9 wherein a terminal amino acid of the linker is lysine.

11. The reagent of claim 10 wherein the linker comprises the sequence GGGSK set out in SEQ ID NO:

18.

14. A composition comprising the reagent of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, and a pharmaceutically acceptable excipient.

15. A method for detecting colon pre-cancer, early cancer or cancer in a patient comprising the steps of administering the reagent of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 to the colon of the patient and detecting binding of the reagent to pre-cancer, early cancer or cancer colon cells.

16. A method for detecting pre-cancer, early cancer or cancer in a patient comprising the steps of administering the reagent of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 to the patient and detecting binding of the reagent.

17. A method of determining the effectiveness of a treatment for cancer and/or cancer metastasis, or recurrence of cancer in a patient comprising the step of administering the reagent of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 to the patient, visualizing a first amount of cells labeled with the reagent, and comparing the first amount to a previously-visualized second amount of cells labeled with the reagent,

wherein a decrease in the first amount cells labeled relative to the previously-visualized second amount of cells labeled is indicative of effective treatment.

18. The method of claim 17 further comprising obtaining a biopsy of the cells labeled by the reagent.

25. A kit for administering the composition of claim 14 to a patient in need thereof, said kit comprising the composition of claim 14, instructions for use of the composition and a device for administering the composition to the patient.

12. The reagent of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 comprising a therapeutic moiety attached to the peptide.

13. The reagent of claim 12 wherein the therapeutic moiety is chemotherapeutic agent.

19. A method for delivering a therapeutic moiety to dysplastic cells of a patient comprising the step of administering the reagent of claim 12 to the patient.

24. A method for delivering a therapeutic moiety to early cancer cells or cancer cells of a patient comprising the step of administering the reagent of claim 12 to the patient.

26. A peptide consisting of the amino acid sequence QRHKPRE (SEQ ID NO:

1), HAHRSWS (SEQ ID NO;

     2), TYPISFM (SEQ ID NO;

     4), SHRNRPRNTQPS (SEQ ID NO;

     8), NRHKPREKTFTD (SEQ ID NO;

     9), TAVPLKRSSVTI (SEQ ID NO;

     10), GHTANRQPWPND (SEQ ID NO;

     11), LSLTRTRHRNTR (SEQ ID NO;

     12), RHRDTQNHRPTN (SEQ ID NO;

     13), ARHRPKLPYTHT (SEQ ID NO;

     14) or KRPRTRNKDERR (SEQ ID NO;

     15).