Antibody-conjugates with improved therapeutic index for targeting CD30 tumours and method for improving therapeutic index of antibody-conjugates
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
Assignees
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Publication Number
US-11590239-B2
Publication Date
2023-02-28
Expiration Date
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(F1)x-P in the presence of a catalyst, wherein S(F1)x is a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q1, x is 1 or 2 and P is a nucleoside mono- or diphosphate, and wherein the catalyst is capable of transferring the S(F1)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 Q1 capable of reacting with functional group F1 and a target molecule D connected to Q1 via a linker L2 to obtain the antibody-conjugate wherein linker L comprises S—Z3-L2 and wherein Z3 is a connecting group resulting from the reaction between Q1 and F1. 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.
Core Innovation
The invention relates to a method for treating CD30-positive cancer by administering an antibody-conjugate to a subject in need thereof. The antibody-conjugate comprises an antibody AB connected to a target molecule D via a linker L, and the antibody AB is capable of targeting CD30-expressing tumours. The resulting antibody-conjugate has a structure consistent with the defined framework.
In the first stage, a glycoprotein comprising 1-4 core N-acetylglucosamine moieties is contacted with a compound of the formula S(F1)x-P in the presence of a catalyst. S(F1)x is defined as a sugar derivative comprising x functional groups F1 capable of reacting with a functional group Q1, where x is 1 or 2, and P is a nucleoside mono- or diphosphate. The catalyst transfers the S(F1)x moiety to the core-GlcNAc moiety to obtain a modified antibody according to Formula (24).
In the second stage, the modified antibody is reacted with a linker-conjugate comprising a functional group Q1 capable of reacting with functional group F1, where the target molecule D is connected to Q1 via a linker L2. The resulting antibody-conjugate includes a linker L comprising S—Z3-L2, where Z3 is a connecting group resulting from the reaction between Q1 and F1. The described linker-conjugate system includes Q1 reactive groups and connecting groups Z1, Z2, and Z3, with spacer moieties Sp1–Sp4.
Claims Coverage
One independent claim is identified, directed to a method of treating CD30-positive cancer using a CD30-targeting antibody-conjugate. The claim includes three inventive feature sets: catalyst-mediated transfer of a defined S(F1)x moiety onto core GlcNAc, subsequent Q1–F1 coupling that defines linker L through S—Z3-L2, and administration of the resulting antibody-conjugate for treatment.
CD30-positive cancer treatment with defined antibody-linker architecture
A method for treating CD30-positive cancer by administering to a subject an antibody-conjugate comprising an antibody AB connected to a target molecule D via a linker L, where the antibody-conjugate is obtainable by the two-stage modification and coupling sequence and the antibody AB targets CD30-expressing tumours.
Catalyst-mediated transfer of S(F1)x-P to core GlcNAc
Obtaining a modified antibody by contacting a glycoprotein comprising 1-4 core N-acetylglucosamine moieties with a compound of the formula S(F1)x-P in the presence of a catalyst, where S(F1)x is a sugar derivative comprising x functional groups F1 capable of reacting with Q1, x is 1 or 2, and P is a nucleoside mono- or diphosphate.
Q1–F1 linker-conjugate coupling to form L as S—Z3-L2
Reacting the modified antibody with a linker-conjugate comprising Q1 capable of reacting with F1 and a target molecule D connected to Q1 via linker L2 to obtain the antibody-conjugate, where linker L comprises S—Z3-L2 and Z3 is the connecting group resulting from the reaction between Q1 and F1.
Claim coverage centers on making a CD30-targeting antibody-conjugate through catalyst-mediated installation of a defined sugar derivative on core GlcNAc, followed by Q1–F1 coupling to form a linker L that includes S—Z3-L2 while connecting the target molecule D to the antibody.
Stated Advantages
Improved therapeutic index
Increased stability (reduced degradation)
Decreased aggregation
Documented Applications
Treating CD30-positive cancer by administering an antibody-conjugate targeting CD30-expressing tumours.
Treating disorders selected from lymphoma, leukaemia, germ cell cancer, graft-versus-host disease (GvHD), and lupus.
Therapeutic effects include preventing proliferation of CD30-expressing cells and/or containing and reducing CD30-expressing cells.
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