Pyrrolobenzodiazepine antibody conjugates

Patent metadata

Field	Value
Publication number	US-11517626-B2
Application number	US-201716076595-A
Country	US
Kind code	B2
Filing date	Feb 10, 2017
Priority date	Feb 10, 2016
Publication date	Dec 6, 2022
Grant date	Dec 6, 2022

Abstract

A conjugate of formula I:

L-(D L ) P   (1)

wherein L is a Ligand unit, D L is a Drug Linker unit of formula II:

wherein either:
(a) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(b) R 11 is OH, and R 10 is:

p is an integer of from 1 to 20.

First claim

The invention claimed is:

1. A conjugate of formula I:
L-(D L ) P   (I)

wherein L is a Ligand unit, D L is a Drug Linker unit of formula II:

wherein
either:
(a) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(b) R 11 is OH, and R 10 is:

p is an integer of from 1 to 20 and wherein the Ligand Unit is an antibody or an active fragment thereof.

2. A conjugate according to claim 1 , wherein D L is D L -A:

3. A conjugate according to claim 1 , wherein D L is D L -B:

4. The conjugate according to claim 1 , wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

5. The conjugate according to claim 1 , wherein the antibody or antibody fragment is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(88):
(1) BMPR1B;
(2) E16;
(3) STEAP1;
(4) 0772P;
(5) MPF;
(6) Napi3b;
(7) Sema 5b;
(8) PSCA h1g;
(9) ETBR;
(10) MSG783;
(11) STEAP2;
(12) TrpM4;
(13) CRIPTO;
(14) CD21;
(15) CD79b;
(16) FcRH2;
(17) HER2;
(18) NCA;
(19) MDP;
(20) IL20R-alpha;
(21) Brevican;
(22) EphB2R;
(23) ASLG659;
(24) PSCA;
(25) GEDA;
(26) BAFF-R;
(27) CD22;
(28) CD79a;
(29) CXCR5;
(30) HLA-DOB;
(31) P2X5;
(32) CD72;
(33) LY64;
(34) FcRH1;
(35) IRTA2;
(36) TENB2;
(37) PSMA-FOLH1;
(38) SST;
(38.1) SSTR2;
(38.2) SSTR5;
(38.3) SSTR1;
(38.4) SSTR3;
(38.5) SSTR4;
(39) ITGAV;
(40) ITGB6;
(41) CEACAM5;
(42) MET;
(43) MUC1;
(44) CA9;
(45) EGFRvIII;
(46) CD33;
(47) CD19;
(48) IL2RA;
(49) AXL;
(50) CD30-TNFRSF8;
(51) BCMA-TNFRSF17;
(52) CT Ags-CTA;
(53) CD174 (Lewis Y)-FUT3;
(54) CLEC14A;
(55) GRP78-HSPA5;
(56) CD70;
(57) Stem Cell specific antigens;
(58) ASG-5;
(59) ENPP3;
(60) PRR4;
(61) GCC-GUCY2C;
(62) Liv-1-SLC39A6;
(63) 5T4;
(64) CD56-NCMA1;
(65) CanAg;
(66) FOLR1;
(67) GPNMB;
(68) TIM-1-HAVCR1;
(69) RG-1/Prostate tumor target Mindin-Mindin/RG-1;
(70) B7-H4-VTCN1;
(71) PTK7;
(72) CD37;
(73) CD138-SDC1;
(74) CD74;
(75) Claudins-CLs;
(76) EGFR;
(77) Her3;
(78) RON-MST1R;
(79) EPHA2;
(80) CD20-MS4A1;
(81) Tenascin C-TNC;
(82) FAP;
(83) DKK-1;
(84) CD52;
(85) CS1-SLAMF7;
(86) Endoglin-ENG;
(87) Annexin A1-ANXA1;
(88) V-CAM (CD106)-VCAM1.

6. The conjugate according to claim 1 , wherein the antibody or antibody fragment is a cysteine-engineered antibody.

7. The conjugate according to claim 1 wherein p is an integer from 1 to 8.

8. The conjugate according to claim 7 , wherein p is 1, 2, 3, or 4.

9. A composition comprising a mixture of conjugates according to claim 1 , wherein the average p in the mixture of conjugate compounds is about 1 to about 8.

10. A pharmaceutical composition comprising the conjugate of claim 1 , a pharmaceutically acceptable diluent, carrier or excipient.

11. A method of medical treatment comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition of claim 10 , wherein the method of medical treatment is for treating cancer, wherein the cancer comprises lymphoma, breast cancer, or gastric cancer.

12. The method of claim 11 , wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.

13. A method of treating a mammal having lymphoma, breast cancer, or gastric cancer, comprising administering an effective amount of a conjugate according to claim 1 or a pharmaceutical composition according to claim 10 .

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Dunny Elizabeth
• Masterson Luke

Classifications

• A61K47/6867 Primary

  the tumour determinant being from a cell of a blood cancer · CPC title

• A61K31/5517 Primary

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title