Methods for forming polymer-drug conjugates

• US 8,633,277 B2
• Filed: 03/08/2011
• Issued: 01/21/2014
• Est. Priority Date: 05/23/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Harris, J. Milton, Kozlowski, Antoni, McManus, Samuel P., Bentley, Michael D., Charles, Stephen A.
• Primary Examiner(s): Fubara, Blessing M
• Application Number:
  US13/043,438
• Publication Number:
  US 20110178242A1
• Time in Patent Office: 1,050 Days
• Field of Search: 525/54.1, 525/50, 424/78.27, 424/85.1, 424/85.5, 424/85.7
• US Class Current: 525/54.1
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33337 cyclic
• CPC Class Codes: C08G 65/33344 containing carbamate group

Abstract

Methods for preparing polymer-drug conjugates are provided. The disclosed methods involve polymeric reagents comprising a moiety of atoms arranged in a specific order, wherein the moiety is positioned between a water-soluble polymer and a reactive group. Related methods, compositions, preparations, and so forth are also provided.

Claims

1. A method of preparing a conjugate comprising the step of contacting a polymeric reagent with an active agent under suitable conjugation conditions to thereby provide the conjugate, wherein the polymeric reagent has the following structure

2. The method of claim 1, wherein each R¹ is H.

3. The method of claim 1, wherein each R¹ is an organic radical and is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl.

4. The method of claim 1, wherein each water-soluble polymer is a poly(alkylene oxide).

5. The method of claim 4, wherein each poly(alkylene oxide) is a poly(ethylene glycol).

6. The method of claim 5, wherein each poly(ethylene glycol) is terminally capped with methoxy.

7. The method of claim 5, wherein each poly(ethylene glycol) has a molecular weight of from about 100 Daltons to about 100,000 Daltons.

8. The method of claim 7, wherein each poly(ethylene glycol) has a molecular weight of from about 1,000 Daltons to about 60,000 Daltons.

9. The method of claim 8, wherein each poly(ethylene glycol) has a molecular weight of from about 2,000 Daltons to about 50,000 Daltons.

10. The method of claim 1, wherein the reactive group reactive group is selected from the group consisting of hydroxyl, ester, ester, orthoester, carbonate, carbonate, acetal, aldehyde, aldehyde hydrate, ketone, vinyl ketone, ketone hydrate, thione, monothiohydrate, dithiohydrate, hemiketal, monothioketal hemiketal, dithiohemiketal, ketal, dithioketal, alkenyl, acrylate, methacrylate, acrylamide, sulfone, sulfone, amine, hydrazide, thiol, disulfide, thiol hydrate, carboxylic acid, isocyanate, isothiocyanate, maleimide, succinimide, benzotriazole, vinylsulfone, chloroethylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxals, diones, mesylates, tosylates, thiosulfonate, tresylate, silane, —

(CH₂)_rCO₂H, —

(CH₂)_r′

CO₂NS, —

(CH₂)_r′

CO₂Bt, —

(CH₂)_rCH(OR)₂, —

(CH₂)_rCHO, —

(CH₂)₂—

N H₂, —

(CH₂)_rM, —

(CH₂)_r—

S—

SO₂—

R, where r is 1-5, r′

is 0-5, R is aryl or alkyl, NS is N-succinimidyl, Bt is 1-benzotriazolyl, and M is N-maleimidyl, and protected and activated forms of any of the foregoing.

11. The method of claim 1, wherein the polymeric reagent has the following structure:

12. The method of claim 1, wherein the polymeric reagent has the following structure:

13. The method of claim 1, wherein the polymeric reagent has a structure selected from the group consisting of

14. The method of claim 1, wherein the polymeric reagent has a structure selected from the group consisting of:

15. The method of claim 1, wherein the polymeric reagent has a structure selected from the group consisting of:

16. The method of claim 1, wherein the polymeric reagent has a structure selected from the group consisting of:

17. The method of claim 1, wherein the active agent is a protein.

18. The method of claim 1, wherein the active agent is selected from the group consisting of erythropoietin, granulocyte-colony stimulating factor, interferon-α

, human growth hormone, interferon-β

, follicle stimulating hormone, Factor VIII, B-domain deleted Factor VIII, desmopressin and amdoxivir.