Peptidomimetic compounds and antibody-drug conjugates thereof

Patent metadata

Field	Value
Publication number	US-10124069-B2
Application number	US-201615182429-A
Country	US
Kind code	B2
Filing date	Jun 14, 2016
Priority date	Dec 16, 2013
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.

First claim

The invention claimed is:

1. An antibody-drug conjugate represented by Formula (I)
Ab-(L-D) p ,
Ab is an antibody, wherein the antibody binds to one or more of polypeptides selected from the group consisting of:
CLL1;
BMPR1B;
E16;
STEAP1;
0772P;
MPF;
NaPi2b;
Sema 5b;
PSCA hlg;
ETBR;
MSG783;
STEAP2;
TrpM4;
CRIPTO;
CD21;
CD79b;
FcRH2;
HER2;
NCA;
MDP;
IL20Rα;
Brevican;
EphB2R;
ASLG659;
PSCA;
GEDA;
BAFF-R;
CD22;
CD79a;
CXCR5;
HLA-DOB;
P2X5;
CD72;
LY64;
FcRH1;
IRTA2;
TENB2;
PMEL17;
TMEFF 1;
GDNF-Ra1;
TMEM46;
Ly6G6D;
LGR5;
RET;
LY6K;
GPR19;
GPR54;
ASPHD1;
Tyrosinase;
TMEM118;
GPR172A;
MUC16 and
CD33;
L is a peptidomimetic linker represented by the following formula
-Str-(PM)-Sp-

wherein
Str is a stretcher unit covalently attached to Ab; having the formulas:

wherein R 6 is selected from the group consisting of C 1 -C 10 alkylene, C 1 -C 10 alkenyl, C 3 -C 8 cycloalkyl, (C 1 -C 8 alkylene)O—, and C 1 -C 10 alkyleneC(O)N(R a )—C 2 -C 6 alkylene, where each alkylene may be substituted by one to five substituents selected from the group consisting of halo, trifluoromethyl, difluoromethyl, amino, alkylamino, cyano, sulfonyl, sulfonamide, sulfoxide, hydroxy, alkoxy, ester, carboxylic acid, alkylthio, C 3 -C 8 cycloalkyl, C 4 -C 7 heterocycloalkyl, heteroarylalkyl, aryl arylalkyl, heteroarylalkyl and heteroaryl each R a is independently H or C 1 -C 6 alkyl; or

wherein R 7 is selected from C 1 -C 10 alkylene, C 1 -C 10 alkenyl, (C 1 -C 10 alkylene)O—, N(R c )—(C 2 -C 6 alkylene)-N(R c ) or N(R c )—(C 2 -C 6 alkylene); where each R c is independently H or C 1 -C 6 alkyl;
Sp is a bond or spacer unit covalently attached to a drug moiety selected from —C 1 -C 6 alkylene-C(O)NH— or —Ar—R b —, wherein Ar is aryl or heteroaryl, and R b is (C 1 -C 10 alkylene)O—;
PM is a non-peptide chemical moiety-having the formula:

R 1 is C 1 -C 10 alkyl, C 1 -C 10 alkenyl, (C 1 -C 10 alkyl)NHC(NH)NH 2 or (C 1 -C 10 alkyl)NHC(O)NH 2 ;
R 4 and R 5 are each independently C 1 -C 10 alkyl, C 1 -C 10 alkenyl, arylalkyl, heteroarylalkyl, (C 1 -C 10 alkyl)OCH 2 —, or R 4 and R 5 together may form a C 3 -C 7 cycloalkyl ring;
p is an integer from 1 to 8; and
D is a dimer drug moiety having the formula:

wherein
R 11 is selected from H, P(O) 3 H 2 , C(O)NR aa R bb , or a bond to L;
R 22 is selected from H, P(O) 3 H 2 , C(O)NR aa R bb , or a bond to L;
R aa and R bb are independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more F,
or R aa and R bb form a five or six membered heterocycloalkyl group;
T is a tether group selected from C 3 -C 12 alkylene, Y′, (C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene), (C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene)-Y 1 —(C 1 -C 6 alkylene), (C 2 -C 6 alkenylene)-Y 1 —(C 2 -C 6 alkenylene), or (C 2 -C 6 alkynylene)-Y 1 —(C 2 -C 6 alkynylene);
where Y 1 is independently selected from O, S, NR 11 , aryl, or heteroaryl;
where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C 1 -C 6 alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC(O)(C 1 -C 6 alkylene); OP(O) 3 H 2 , or C 1 -C 6 alkyl, where alkyl is optionally substituted with one or more F, m is 0 or 1;
or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to L, wherein the bond to L may connect through one of the optional substituents;
D′ is a drug moiety selected from:

where the wavy line indicates the site of attachment to T;
X 1 and X 2 are independently selected from O or NR 33 , where R 33 is selected from H, C(O), or C 1 -C 6 alkyl, optionally substituted with one or more F, or X 1 and X 2 are each independently absent;
R 44 is H, CO 2 R, C(O), or a bond to L, where R is C 1 -C 6 alkyl or benzyl; and
R 55 is H or C 1 -C 6 alkyl.

2. The antibody-drug conjugate of claim 1 represented by the following formula:

wherein
p is 1, 2, 3 or 4.

3. The antibody-drug conjugate compound of claim 2 ,
wherein
Str is a chemical moiety represented by the following formula:

and R 6 is C 1 -C 6 alkylene.

4. The antibody-drug conjugate compound of claim 1 , which is represented by the following formula:

wherein
p is 1, 2, 3 or 4;
R 1 is C 1 -C 6 alkyl-NH 2 , (C 1 -C 6 alkyl)NHC(NH)NH 2 or (C 1 -C 6 alkyl)NHC(O)NH 2 ; and
R 4 and R 5 form a C 3 -C 7 cycloalkyl ring.

5. The antibody-drug conjugate of claim 1 , which is represented by the following formula:

wherein,
Ab is an antibody that binds to a target selected from Her2, CLL1, CD33, CD22 or NaPi2b;
p is 1-4;
R 1 is C 1 -C 6 alkyl-NH 2 , (C 1 -C 6 alkyl)NHC(NH)NH 2 or (C 1 -C 6 alkyl)NHC(O)NH 2 ; and
R 20 is H or Me.

6. The antibody-drug conjugate of claim 1 , which is represented by the following formula:

wherein,
Ab is an antibody that binds to a target selected from Her2, CLL1, CD33, CD22 or NaPi2b;
p is 1-4;
R 1 is C 1 -C 6 alkyl-NH 2 , (C 1 -C 6 alkyl)NHC(NH)NH 2 or (C 1 -C 6 alkyl)NHC(O)NH 2 ; and
R 20 is H or Me.

7. The antibody-drug conjugate of claim 1 , which is represented by the following formula:

wherein,
Ab is an antibody that binds to a target selected from Her2, CLL1, CD33, CD22 or NaPi2b;
P is 1-4; and
R 1 is C 1 -C 6 alkyl-NH 2 , (C 1 -C 6 alkyl)NHC(NH)NH 2 or (C 1 -C 6 alkyl)NHC(O)NH 2 .

8. The antibody-drug conjugate of claim 1 , which is represented by the following formula:

wherein,
Ab is an antibody that binds to a target selected from Her2, CLL1, CD33, CD22 or NaPi2b;
P is 1-4;
R 1 is C 1 -C 6 alkyl-NH 2 , (C 1 -C 6 alkyl)NHC(NH)NH 2 or (C 1 -C 6 alkyl)NHC(O)NH 2 ;
X 1 and X 2 are each independently absent or O; and
each R 11 is independently C(O)N-piperazine(CH 3 ) or P(O) 3 H 2 .

9. A non-peptide compound of Formula (I)(B)(LD1):

wherein
Str is a stretcher unit which can be covalently attached to an antibody, having the formula:

Assignees

• Genentech Inc

Inventors

• Lee Ho Huat
• Tercel Moana
• Flygare John A
• Gunzner-Toste Janet
• Pillow Thomas H
• Safina Brian
• Staben Leanna
• Verma Vishal
• Wei Binqing
• Zhao Guiling

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• C07K16/2863

  against receptors for growth factors, growth regulators · CPC title