Protein-polymer-drug conjugates

Patent metadata

Field	Value
Publication number	US-9770519-B2
Application number	US-201514834159-A
Country	US
Kind code	B2
Filing date	Aug 24, 2015
Priority date	Jun 10, 2011
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric carrier substituted with one or more -L D -D, the protein based recognition-molecule being connected to the polymeric carrier by L P . Each occurrence of D is independently a therapeutic agent having a molecular weight ≦5 kDa. L D and L P are linkers connecting the therapeutic agent and PBRM to the polymeric carrier respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.

First claim

What is claimed is:

1. A method of preparing a polymeric scaffold useful to conjugate with a protein based recognition-molecule (PBRM) wherein the polymeric scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) and is substituted both with one or more

and with one or more

the method comprising:
(a) providing a PHF carrier that is substituted with one or more —R L1 —C (═O)-L D1 , wherein R L1 is connected to an oxygen atom of the PHF, L D1 is a carbonyl-containing moiety and R L1 is absent, an alkyl, a heteroalkyl, a cycloalkyl, or a heterocycloalkyl group; and
(b) reacting the PHF carrier with a compound containing an L P2 moiety to produce a polymeric carrier substituted with one or more

 in which L P2 is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of the PBRM, and

 denotes direct or indirect attachment of L P2 to L D1 ; and
(c) reacting the PHF carrier with D which contains a functional group that is capable of forming a covalent bond with —R L1 —C(═O)-L D1 to produce a polymeric carrier substituted with one or more

 wherein

 denotes direct or indirect attachment of D to L D1 , and D is a therapeutic agent having a molecular weight ≦5 kDa.

2. The method of claim 1 , wherein L D1 is —X—(CH 2 ) v —COOH with X directly connected to the carbonyl group of —R L1 —C(═O)-L D1 , in which X is CH 2 , O, or NH, and v is an integer from 1 to 6.

3. The method of claim 1 , wherein L P2 comprises a terminal Group W P , in which each W P independently is:

in which R 1K is a leaving group, R 1A is a sulfur protecting group, and ring A is cycloalkyl or heterocycloalkyl, and R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

4. The method of claim 3 , wherein R 1A is

in which r is 1 or 2 and each of R s1 , R s2 , and R s3 is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

5. The method of claim 1 , wherein L P2 contains a functional group that is selected from —SR p , —S—S-LG, maleimido, and halo, in which LG is a leaving group and R P is H or a sulfur protecting group.

6. The method of claim 1 , wherein D is an anticancer drug selected from vinca alkaloids, non-natural camptothecin compounds, auristatins, tubulysins, duocarmycins, calicheamicins, maytansinoids, topoisomerase I inhibitors, kinase inhibitors, Kinesin Spindle Protein (KSP) inhibitors, pyrrolobenzodiazepines, DNA-binding or alkylating drugs, RNA polymerase inhibitors, protein synthesis inhibitors and analogs thereof.

7. The method of claim 1 , wherein step (b) is performed before step (c).

8. The method of claim 1 , wherein step (c) is performed before step (b).

9. The method of claim 1 , wherein steps (b) and (c) are performed simultaneously.

10. The method of claim 1 , wherein R L1 is absent.

11. The method of claim 1 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 40 kDa.

12. The method of claim 1 , wherein the PHF has molecular weight ranging from about 20 kDa to about 300 kDa.

13. The method of claim 1 , further comprising reacting the polymeric scaffold that is substituted both with one or more

and with one or more

with a PBRM.

14. A method of preparing a polymeric scaffold useful to conjugate with a protein based recognition-molecule (PBRM) wherein the polymeric scaffold comprises poly(1- hydroxymethylethylene hydroxymethyl-formal) (PHF) and is substituted both with one or more

and with one or more

the method comprising:
(a) providing a PHF carrier that is substituted with one or more —R L1 —C(═O)-L D1 and one or more

 wherein R L1 is connected to an oxygen atom of the PHF, L D1 is a carbonyl-containing moiety, R L1 absent, an alkyl, a heteroalkyl, a cycloalkyl, or a heterocycloalkyl group, L P2 is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of the PBRM, and

 denotes direct or indirect attachment of L P2 to L D1 ; and
(b) reacting the PHF carrier with D which contains a functional group that is capable of forming a covalent bond with —R L1 13 C(═O)-L D1 to produce the polymeric scaffold that is substituted both with one or more

 and with one or more

 wherein

 denotes direct or indirect attachment of D to L D1 , and D is a therapeutic agent having a molecular weight ≦5 kDa.

15. The method of claim 14 , wherein L D1 is —X—(CH 2 ) v —COOH with X directly connected to the carbonyl group of —R L1 —C(═O)-L D1 , in which X is CH 2 , O, or NH, and v is an integer from 1 to 6.

16. The method of claim 14 , wherein L P2 comprises a terminal group W P , in which each W P independently is:

in which R 1K is a leaving group, R 1A is a sulfur protecting group, and ring A is cycloalkyl or heterocycloalkyl, and R 1J is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

17. The method of claim 16 , wherein R 1A is

in which r is 1 or 2 and each of R s1 , R s2 , R s3 is hydrogen, an aliphatic, heteroaliphatic, carbocyclic, or heterocycloalkyl moiety.

18. The method of claim 14 , wherein L P2 contains a functional group that is selected from —SR P , —S—S-LG, maleimido, and halo, in which LG is a leaving group and R P is H or a sulfur protect

Assignees

• Mersana Therapeutics Inc

Inventors

• Yurkovetskiy Aleksandr
• Yin Mao
• Lowinger Timothy B
• Thomas Joshua D
• Hammond Charles E
• Stevenson Cheri A
• Bodyak Natalya D
• Conlon Patrick R
• Gumerov Dmitry R

Classifications

• C08G65/3324

  cyclic · CPC title

• C08L71/00

  Compositions of polyethers obtained by reactions forming an ether link in the main chain (of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06); Compositions of derivatives of such polymers · CPC title

• C08G65/3348

  containing nitrogen in addition to sulfur · CPC title

• A61K47/6883

  Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy · CPC title

• C08G6/00

  Condensation polymers of aldehydes or ketones only · CPC title