IP Library Granted Patent US 9,821,074
Granted Patent B2
US 9,821,074 · App. 14/208,374 · Granted Nov 21, 2017

Pyrrolobenzodiazepines and conjugates thereof

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Quick Facts
Patent No.
US 9,821,074
App. No.
14/208,374
Granted
Nov 21, 2017
Kind
B2
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).

Claims (15)

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.

Assignments (5)
CORRECTIVE ASSIGNMENT TO CORRECT THE POSTAL CODE OF THE ASSIGNEE PREVIOUSLY RECORDED AT REEL: 036932 FRAME: 0278. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT . Recorded Apr 11, 2017
From: SPIROGEN SÀRL
To: MEDIMMUNE LIMITED
Reel/Frame 042242/0389 →
CONFIRMATORY ASSIGNMENT Recorded Oct 23, 2015
From: SPIROGEN SÀRL
To: MEDIMMUNE LIMITED
Reel/Frame 036932/0278 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 23, 2014
From: HOWARD, PHILIP WILSON
To: SPIROGEN LIMITED
Reel/Frame 032739/0435 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 23, 2014
From: SPIROGEN LIMITED
To: SPIROGEN SARL
Reel/Frame 032739/0541 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 23, 2014
From: FLYGARE, JOHN A.; PILLOW, THOMAS; WEI, BINQING
To: GENENTECH, INC.
Reel/Frame 032739/0779 →