Protein-polymer-drug conjugates

Patent metadata

Field	Value
Publication number	US-9943609-B2
Application number	US-201615001119-A
Country	US
Kind code	B2
Filing date	Jan 19, 2016
Priority date	Jun 10, 2011
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

Auristatin compounds and conjugates thereof are 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 an Auristatin compound. 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 polymeric scaffold of Formula (Ia) useful to conjugate with an antibody:

wherein:
the scaffold comprises poly(l-hydroxymethylethylene hydroxymethyl-formal) (PHF) having a molecular weight ranging from 2 kDa to 40 kDa;
each occurrence of D is independently a non-natural camptothecin compound;
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 an antibody, 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 antibody, 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.

2. The scaffold of claim 1 , 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.

3. The scaffold of claim 1 , 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.

4. The scaffold of claim 1 , wherein the functional group of L P2 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.

5. The scaffold of claim 1 , 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.

6. The scaffold of claim 1 , wherein L P2 contains a biodegradable bond.

7. The scaffold of claim 1 , wherein

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.

8. The scaffold of claim 7 , 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.

9. The scaffold of claim 1 , further comprising an antibody connected to the scaffold via L P2 .

10. The scaffold of claim 9 , wherein the antibody has a molecular weight of greater than 40 kDa.

11. The scaffold of claim 9 , wherein the antibody has a molecular weight of greater than 80 kDa.

12. The scaffold of claim 1 , wherein each occurrence of D, before conjugating to the scaffold, is a compound of Formula (VII):

wherein:
R 24 is —H, —Cl, —F, —OH or alkyl; or R 24 and R 25 , taken together with the carbon atoms to which they attach, form a five- or six-membered ring;

R 25 is —H, —F, —OH, —CH 3 , —CH═N—O-t-Butyl, —CH 2 CH 2 Si(CH 3 ) 3 , —Si((CH 3 ) 2 )-t-butyl, —O—C(O)—R 29 ;
R 29 is NH 2 , —R 28 —C 1-6 alkyl-R 22 , 5 to 12-membered heterocycloalkyl, R 28 —C 5-12 heterocycloalkyl-C 1-6 alkyl-R 22 or —R 28 —C 1-6 alkyl-C 6-12 aryl-C 1-6 alkyl-R 22 ;
R 26 is —H, —CH 2 —N(CH 3 ) 2 , NH 2 , or NO 2 ;
R 27 is ethyl, N-methyl piperidine, cycloalkyl, —CH 2 CH 2 NHCH(CH 3 ) 2 , or —N-4-methylcyclohexylamine;
R 79 is —H or —C(O)—R 28 —[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, —NH 2 , —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;
or R 26 and R 27 when taken together with the two carbon atoms to which they attach and the third carbon atom connecting the two carbon atoms form an optionally substituted six-membered ring;
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;
f is an integer from 1 to 12;
u is an integer 0 or 1;
w is an integer 0 or 1; and
the compound of Formula (VII) contains at least one of R 29 and R 79 .

13. The scaffold of claim 12 , wherein each occurrence of D is a compound of Formula (VIII) or Formula (XXV):

wherein:
R 30 is —NH 2 , —R 28 —C 1-6 alkyl-R 22 , 5 to 12-membered heterocycloalkyl, R 28 —C 5-12 heterocycloalkyl-C 1-6 alkyl-R 22 or —R 28 —C 1-6 alkyl-C 6-12 aryl-C 1-6 alkyl-R 22 ;

R 28 is absent, NH or oxygen;
R 22 is —OH, —NH 2 , —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;
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.

14. The scaffold of claim 13 , wherein R 30 is any one of the following structures:

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 Dimitry R

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K7/02

  Linear peptides containing at least one abnormal peptide link · CPC title

• A61K47/59 Primary

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title

• C07K5/02 Primary

  containing at least one abnormal peptide link · CPC title