Antibody-conjugates with improved therapeutic index for targeting CD30 tumours and method for improving therapeutic index of antibody-conjugates

Patent metadata

Field	Value
Publication number	US-11590239-B2
Application number	US-201716076281-A
Country	US
Kind code	B2
Filing date	Feb 8, 2017
Priority date	Feb 8, 2016
Publication date	Feb 28, 2023
Grant date	Feb 28, 2023

Abstract

The present invention concerns novel and improved antibody-conjugates for targeting CD30. The inventors found that when antibody-conjugates were prepared using a specific mode of conjugation, they exhibit an improved therapeutic index. The mode of conjugation comprises a first step (i) of contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F 1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x moiety to the core-GlcNAc moiety, to obtain a modified antibody; and a second step (ii) of reacting the modified antibody with a linker-conjugate comprising a functional group Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises S—Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 . The invention also relates to a use for improving the therapeutic index of an antibody-conjugate and to a method for targeting CD30-expressing cells.

First claim

The invention claimed is:

1. A method for treating CD30-positive cancer, comprising administering to a subject in need thereof an antibody-conjugate, comprising an antibody AB connected to a target molecule D via a linker L, wherein the antibody-conjugate is obtainable by:
contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F 1 ) x -P in the presence of a catalyst, wherein S(F 1 ) x is a sugar derivative comprising x functional groups F 1 capable of reacting with a functional group Q 1 , x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F 1 ) x moiety to the core-GlcNAc moiety, to obtain a modified antibody according to Formula (24):

wherein S(F 1 ) x and x are as defined above; AB represents an antibody; GlcNAc is N-acetylglucosamine; Fuc is fucose; b is 0 or 1; and y is 1, 2, 3 or 4; and
(ii) reacting the modified antibody with a linker-conjugate comprising a functional group Q 1 capable of reacting with functional group F 1 and a target molecule D connected to Q 1 via a linker L 2 to obtain the antibody-conjugate wherein linker L comprises
S—Z 3 -L 2 and wherein Z 3 is a connecting group resulting from the reaction between Q 1 and F 1 ,
wherein antibody AB is capable of targeting CD30-expressing tumours and the antibody-conjugate has structure:

2. The method according to claim 1 , wherein the treating CD30-positive cancer includes preventing the proliferation of CD30-expressing cells, containing and reducing CD30-expressing cells, or a combination thereof.

3. The method according to claim 1 , wherein the subject suffers from a disorder selected from lymphoma, leukaemia, germ cell cancer, graft-versus-host disease (GvHD) and lupus.

4. The method according to claim 1 , wherein x is 1 or 2.

5. The method according to claim 1 , wherein S(F 1 ) x is 6-azido-6-deoxy-N-acetylgalactosamine.

6. The method according to claim 4 , wherein x is 1.

7. The method according to claim 1 , wherein the antibody is brentuximab or iratumumab.

8. The method according to claim 1 , wherein the antibody is iratumumab.

9. The method according to claim 3 wherein the subject suffers from disorders selected from the group consisting of Hodgkin's lymphoma (HL), non-Hodgkin lymphoma (NHL), anaplastic large-cell lymphoma (ALCL), large B-cell lymphoma, paediatric lymphoma, T-cell lymphoma, enteropathy-associated T-cell lymphoma (EATL), acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), mast cell leukaemia, and systemic lupus erythematosus (SLE).

Assignees

• Synaffix Bv

Inventors

• Van Berkel Sander Sebastiaan
• Verkade Jorge Merijn Mathieu
• Wijdeven Maria Antonia
• Heesbeen Ryan
• Van De Sande Petrus Josephus Jacobus Maria
• Gvan Eel Remon
• Janssen Brian Maria Gerardus
• Hurkmans Inge Catharina Josephina
• Van Delft Floris Louis

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/68033

  the drug being a maytansine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6889 Primary

  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