High affinity CXCR4 selective binding conjugate and method for using the same

• US 10,639,379 B2
• Filed: 02/17/2018
• Issued: 05/05/2020
• Est. Priority Date: 09/05/2017
• Status: Active Grant

• Current Assignee: Mainline Biosciences Co.
• Original Assignee: Mainline Biosciences LLC
• Inventors: Zhang, Junge, Yan, Liang Zeng
• Primary Examiner(s): Alstrum-Acevedo, James H
• Assistant Examiner(s): Miknis, Zachary J
• Application Number:
  US15/898,434
• Publication Number:
  US 20190255185A1
• Time in Patent Office: 808 Days
• Field of Search: None
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 47/00 Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/521 Chemokines
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• 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 2333/715 for cytokines; for lymphokines; for interferons
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds

Abstract

The present invention provides a compound that can be used for targeted drug delivery, imaging a patient, or diagnosing a subject for a clinical condition which is believed to be associated with overexpression and/or upregulation of CXCR4. In particular, the present invention provides a high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the Formula: P-(L-A)_n (I) or a pharmaceutically acceptable salt thereof, and a method for using and producing the same. The high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the invention is useful in diagnosing, treating or imaging a patient. In compound of Formula (I), n is an integer from 1 to the sum of (the total number of amino acid resides in P and the total number of side-chain functional group in the amino acid residue of P); each A is independently a diagnostic agent, a therapeutic agent, or an imaging agent; L is a linker or absent; and P is a high affinity CXCR4 selective binding peptidyl ligand. In particular, the invention provides to a targeted drug delivery or imaging a patient or diagnosing a patient for a disease of which overexpression and/or upregulation of CXCR4 is implicated, such as cancers, HIV infection, and immune disorders. Compositions and kits peptide conjugate of Formula I as well as methods for using and producing peptide conjugate of Formula I are disclosed herein.

Claims

1. A high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the Formula:

PL-A)_n 

 

I

or a pharmaceutically acceptable salt thereof, wherein

n is an integer from 1 to about 5 or the sum of (the total number of side-chain functional groups within P)

A is one or more diagnostic agents, therapeutic agents, or imaging agents;

L is a bifunctional linker or absent; and

P is a high affinity CXCR4 selective binding peptidyl ligand of the formula;

2. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein A is attached to the N-terminal end or the C-terminal end of said peptide, or to a function group that is present on the side-chain of the amino acid residue of said peptide, or a combination of any one of the positions thereof.

3. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein said high affinity CXCR4 selective binding ligand peptide conjugate comprises a plurality of A.

4. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein A is an imaging agent.

5. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein A is a diagnostic agent.

6. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein said diagnostic agent is an imaging agent, an isotopic agent, or a radioactive agent.

7. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein said linker comprises a functional group that is capable of releasing A in vivo.

8. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein A is a therapeutic agent.

9. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 8, wherein said therapeutic agent is selected from the group consisting of bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.

10. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein said high affinity CXCR4 selective binding ligand peptide conjugate is:

cyclo[Phe-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-(D-Glu)]-Lys(iPr)-(mini-PEG6)-Cys(S-paclitaxel)-Gly-NH₂ (SEQ ID NO;

3), wherein the cyclic structure is formed between the α

-amino of Phe connected to the side chain of D-Glu;

or

R^a-cyclo[Cys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-Cys]-Lys(iPr)-R^b (SEQ ID NO;

4);

R^a-cyclo[hCys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-Cys]-Lys(iPr)-R^b (SEQ ID NO;

5);

R^a-cyclo[Cys-Tyr-Lys(iPr)-(D-Arg)-2Nal-Gly-hCys]-Lys(iPr)-R^b (SEQ ID NO;

6); and

11. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 of the Formula:

12. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 1, wherein A is selected from the group consisting of HIV protease inhibitors, HIV fusion inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV entry inhibitors, and a combination thereof.

13. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 12, wherein A is HIV fusion inhibitor enfuvirtide.

14. A composition comprising a high affinity CXCR4 selective binding ligand peptide conjugate of claim 1 and a pharmaceutically acceptable carrier, diluent, excipient or a combination thereof.

15. A diagnostic or an imaging kit comprising a high affinity CXCR4 selective binding ligand peptide conjugate (PC) of claim 1, wherein A of Formula I is a diagnostic agent or an imaging agent.

16. A method for imaging cancer cells in a patient comprising:

administering to a patient an imaging effective amount of a high affinity CXCR4 selective binding ligand peptide conjugate of claim 4; and

imaging cancer cells in said patient using an imaging apparatus.

17. A method for treating cancer in a patient, said method comprising administering a therapeutically effective amount of a compound of claim 11 to a cancer patient, wherein A is a cancer drug.

18. A method for treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, said method comprising administering a therapeutically effective amount of a compound of claim 11 to a patient in need of treatment thereof, wherein said cancer is selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin'"'"'s lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia.

19. A high affinity CXCR4 selective binding ligand peptide conjugate (PC) of the Formula:

PL-A)_n 

 

I

or a pharmaceutically acceptable salt thereof, wherein

n is an integer from 2 to about 5 or the sum of (the total number of side-chain functional groups within P)

A is atherapeutic agent;

L is a bifunctional linker or absent; and

P is a high affinity CXCR4 selective binding peptidyl ligand of the formula;

20. The high affinity CXCR4 selective binding ligand peptide conjugate of claim 19, wherein each of said therapeutic agent is independently selected from the group consisting of bleomycin, calicheamicin, daunorubicin, docetaxel, doxorubicin, irinotecan, mertansine, monomethyl auristatin E, paclitaxel, SN-38, tesirine, topotecan, tubulysin, vinca alkaloids, and an analog or derivative thereof, and a combination thereof.