Pyrrolobenzodiazepines and conjugates thereof

Patent metadata

Field	Value
Publication number	US-9821074-B2
Application number	US-201414208374-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 13, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Conjugate compounds of formula (A):

wherein:
R 2 is

 where R 36a and R 36b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester or, when one of R 36a and R 36b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
Y is selected from formulae A1, A2, A3, A4, A5 and A6:

L is a linker connected to a cell binding agent;
CBA is the cell binding agent;
n is an integer selected in the range of 0 to 48;
R A4 is a C 1-6 alkylene group; either
(a) R 10 is H, and R 11 is OH, OR A , where R A is C 1-4 alkyl; or
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 10 is H and R 11 is OSO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R and R′ are each independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;
wherein R 16 , R 17 , R 19 , R 20 , R 21 and R 22 are as defined for R 6 , R 7 , R 9 , R 10 , R 11 and R 2 respectively;
wherein Z is CH or N;
wherein T and T′ are independently selected from a single bond or a C 1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; and

X and X′ are independently selected from O, S and N(H).

First claim

The invention claimed is:

1. An antibody-drug conjugate compound comprising an antibody attached to one or more PBD drug moieties, and prepared by reacting the antibody and a PBD compound selected from:

wherein the antibody binds to one or more tumor-associated antigens or cell-surface receptors selected from:
(4) 0772P (CA125, MUC16);
(6) Napi3b (NAPI-3B, Napi2b, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);
(17) HER2;
(27) CD22 (B-cell receptor CD22-B isoform);
(37) CD33 (CD33 molecule, SIGLEC-3, SIGLEC3, p67; CD33 antigen (gp67); gp67; myeloid cell surface antigen CD33; sialic acid binding Ig-like lectin 3; sialic acid-binding Ig-like lectin); and
(38) LGR5/GPR49.

2. The antibody-drug conjugate compound of claim 1 wherein the antibody is a cysteine-engineered antibody.

3. The antibody-drug conjugate compound of claim 2 wherein the antibody is an antibody which binds to an ErbB receptor.

4. The antibody-drug conjugate compound of claim 3 wherein the antibody is trastuzumab.

5. The antibody-drug conjugate compound of claim 1 wherein the antibody is selected from an anti-HER2 antibody, an anti-CD33 antibody, an anti-LGR5 antibody, an anti-Napi3b antibody, an anti-MUC16 antibody, and an anti-CD22 antibody.

6. The antibody-drug conjugate compound according to claim 1 comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

7. A pharmaceutical composition comprising the antibody-drug conjugate compound of claim 1 , and a pharmaceutically acceptable diluent, carrier or excipient.

8. A method of treating a patient with cancer, comprising administering an effective amount of the pharmaceutical composition according to claim 7 to the patient.

Assignees

• Spirogen Sàrl
• Genentech Inc
• Medimmue Ltd

Inventors

• Howard Philip Wilson
• Flygare John A
• Pillow Thomas
• Wei Binqing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• A61K47/6851

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

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title