Protein-polymer-drug conjugates

Patent metadata

Field	Value
Publication number	US-10603386-B2
Application number	US-201715683300-A
Country	US
Kind code	B2
Filing date	Aug 22, 2017
Priority date	Jun 10, 2011
Publication date	Mar 31, 2020
Grant date	Mar 31, 2020

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 -LD-D, the protein based recognition-molecule being connected to the polymeric carrier by LP. Each occurrence of D is independently a therapeutic agent having a molecular weight≤5 kDa. LD and LP 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 compound of Formula (Xa):

or a pharmaceutically acceptable salt thereof,

wherein:
R 33 is hydrogen, C 1-8 alkyl, C 3-8 carbocycle, C 6-10 aryl, C 1-8 alkyl-C 6-10 aryl, X 1 -(C 3-8 carbocycle), C 3-8 heterocycle or X 1 —(C 3-8 heterocycle);
R 34 is hydrogen, C 1-8 alkyl, C 3-8 carbocycle, C 6-10 aryl, X 1 —C 6-10 aryl, X 1 —(C 3-8 carbocycle), C 3-8 heterocycle or X 1 —(C 3-8 heterocycle);
R 35 is hydrogen or methyl;
or R 34 and R 35 , together with the carbon atom to which they attach form a carbocyclic ring having the formula -(CR 55 R 41 ) b - wherein each of R 55 and R 41 independently is hydrogen or C 1-8 alkyl and b is an integer from 3 to 7;
R 36 is hydrogen or C 1-8 alkyl;
R 37 is hydrogen, C 1-8 alkyl, C 3-8 carbocycle, C 6-10 aryl, -X-C 6-10 aryl, -X 1 —(C 3-8 carbocycle), C 3-8 heterocycle or -X 1 —(C 3-8 heterocycle);
each R 38 independently is hydrogen, OH, C 1-8 alkyl, C 3-8 carbocycle or O-(C 1-8 alkyl);
R 44 is hydrogen or C 1-8 alkyl;

one of R 31 and R 32 is hydrogen or C 1-8 alkyl and the other is:

wherein:
R 83 is hydrogen or CH 3 ;
R 84 is C 1-6 alkyl or C 6-10 aryl;
each R 12 ′ independently is halogen, -C 1-8 alkyl, —O—C 1-8 alkyl, nitro or cyano;
h is an integer from 0 to 4; and

u is an integer 0 or 1;
R 53 is:

 or R 54
R 39 is H, C 1-8 alkyl, C 6-10 aryl, —X 1 —C 6-10 aryl, C 3-8 carbocycle, C 3-8 heterocycle, —X 1 —C 3-8 heterocycle, -C 1-8 alkylene-NH 2 , or (CH 2 ) 2 SCH 3 ,
each X 1 independently is C 1-10 alkylene or C 3-10 cycloalkylene;
R 45 is X 3 —R 42 or NH-R 19 ;
X 3 is O or S;

R 19 is hydrogen, OH, amino group, alkyl amino or -[C(R 20 R 21 )] a -R 22 ;
R 42 is H, an amino group, C 1-6 alkyl amino or -[C(R 20 R 21 )] a -R 22 ;
each of R 20 and R 21 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, hydroxylated C 6-10 aryl, polyhydroxylated C 6-10 aryl, 5 to 12-membered heterocycle, C 3-8 cycloalkyl, hydroxylated C 3-8 cycloalkyl, polyhydroxylated C 3-8 cycloalkyl or a side chain of a natural or unnatural amino acid;
R 22 is —OH, -NHR 23 , —COOH, -R 82 -C(O)(CH 2 )c-C(H)(R 23 )-N(H)(R 23 ), -R 82 -C(O)(CH 2 ) d -(O CH 2 -CH 2 ) f -N(H)(R 23 ) or -R 82 -(C(O)—CH(X 2 )—NH) d -R 77 ;
each R 23 independently is hydrogen, C 1-6 alkyl, C 6-10 aryl, C 3-8 cycloalkyl, —COOH,

or
—COO—C 1-6 alkyl;
X 2 is a side chain of a natural or unnatural amino acid;
R 77 is a hydrogen or X 2 and NR 77 form a nitrogen containing cyclic compound;

R 82 is —NH or oxygen;
R 54 is -C(R 56 ) 2 -C(R 56 ) 2 -C 6-10 aryl, -C(R 56 ) 2 --C(R 56 ) 2 -C 3-8 heterocycle or -C(R 56 ) 2 -C(R 56 ) 2 -C 3-8 carbocycle;
R 56 is independently selected from H, OH, C 1-8 alkyl, C 3-8 carbocycle, -O-C 1-8 alkyl, —O—C(O)-R 29 and -O-R 23 -O—C 1-6 alkyl-NH 2 ;

R 29 is an amino group, 5 to 12-membered heterocycloalkyl, -R 28 -C 1-6 alkyl-R 22 , R 28 -C 5-12 heterocycloalkyl-C 1-6 alkyl-R 22 , -[C(R 20 R 21 )]a-R 22 , or -R 28 -C 1-6 alkyl-C 6-12 aryl-C 1-6 alkyl-R 22 ; or R 29 is R 47 as defined herein;
R 28 is absent, NH or oxygen;
a is an integer from 1 to 6;
c is an integer from 0 to 3;
d is an integer from 1 to 3; and
f is an integer from 1 to 12.

2. The compound of claim 1 , wherein the compound is a compound of Formula (XIa) or Formula (XIb):

wherein:
R 92 is:

R 83 is hydrogen or CH 3 .

3. A polymeric scaffold useful for conjugating a protein based recognition-molecule (PBRM), the scaffold comprising a polymeric carrier and a compound of claim 1 being connected to the polymeric carrier via a biodegradable bond.

4. The scaffold of claim 3 , wherein the polymeric carrier is poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF).

5. The scaffold of claim 3 , wherein the PBRM has a molecular weight of greater than 40 kDa.

6. The scaffold of claim 3 , being of Formula (Ia):

wherein:
the scaffold comprises poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa;
each occurrence of D is independently a compound of claim 1 ;
L D1 is a carbonyl-containing moiety;
each occurrence of

is independently a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; and the

between L D1 and D denotes direct or indirect attachment of D to L D1 ;
each occurrence of

is independently a second linker not yet connected to the PBRM, in which L P2 is a moiety containing a functional group that is yet to form a covalent bond with a functional group of the PBRM, and the

between L D1 and L P2 denotes direct or indirect attachment of L P2 to L D1 , and each occurrence of the second linker is distinct from each occurrence of the first linker;
m is an integer from 1 to 300,
m 1 is an integer from 1 to 140,
m 2 is an integer from 1 to 40,
m 3 is an integer from 1 to 18, and
the sum of m, m 1 , m 2 and m 3 ranges from 15 to about 300.

7. The scaffold of claim 6 , wherein the PHF has a molecular weight ranging from 6 kDa to 20 kDa, m 2 is an integer from 2 to 20, m 3 is an integer from 1 to 9, and m 1 is an integer from 1 to 75, and the sum of m, m 1 , m 2 , and m 3 ranges from about 45 to about 150.

8. The scaffold of claim 6 , wherein the PHF has a molecular weight ranging from 8 kDa to 15 kDa, m 2 is an integer from 2 to 15, m 3 is an integer from 1 to 7, and m 1 is an integer from 1 to 55, and the sum of m, m 1 , m 2 , and m 3 ranges from about 60 to about 110.

9. The scaffold of claim 6 , wherein the functional group of L 2 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.

10. The scaffold of claim 6 , wherein L D1 comprises -X-(CH 2 ) v -C(═O)— with X directly connected to the carbonyl group of

in which X is CH 2 , O, or NH, and v is an integer from 1 to 6.

11. The scaffold of claim 6 , wherein L P2 contains a biodegradable bond.

12. The scaffold of claim 6 , wherein

comprises a terminal group W P , in which each W P independently is:

Assignees

• Mersana Therapeutics Inc

Inventors

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

Classifications

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C08G65/33396

  having oxygen in addition to nitrogen · CPC title

• A61K47/6883

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

• A61K47/58 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title