Combination of antibody-drug conjugate with parp inhibitor

A technology of conjugates and inhibitors, applied in the field of pharmaceutical compositions

Pending Publication Date: 2021-08-17
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this combination has been reported to be problematic in the balance of tolerability and efficacy in clinical studies (non-patent reference 17), and has not yet been established as a standard therapy

Method used

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  • Combination of antibody-drug conjugate with parp inhibitor
  • Combination of antibody-drug conjugate with parp inhibitor
  • Combination of antibody-drug conjugate with parp inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0654] Example 1: Generation of Anti-HER2 Antibody-Drug Conjugate (1)

[0655] According to the production method described in International Publication No. WO 2015 / 115091 and using an anti-HER2 antibody (antibody comprising a heavy chain and a light chain, the heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 , and the light chain consists of the amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2), resulting in an anti-HER2 antibody-drug conjugate, wherein the drug-linker represented by the following formula is via a thioether bond Conjugated with anti-HER2 antibody (hereinafter referred to as "HER2-ADC (1)"):

[0656] [Formula 23]

[0657]

[0658] Where A represents the linking position with the antibody. The DAR of HER2-ADC (1) was 7.7 or 7.8.

Embodiment 2

[0659] Example 2: Generation of Anti-TROP2 Antibody-Drug Conjugate (1)

[0660] According to the production method described in International Publication No. WO 2015 / 098099 and International Publication No. 2017 / 002776 and using an anti-TROP2 antibody (an antibody comprising a heavy chain and a light chain consisting of amino acid residues of SEQ ID NO: 5 5 to 470, and the light chain consists of the amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO:6), resulting in an anti-TROP2 antibody-drug conjugate, wherein represented by The drug-linker was conjugated to the anti-TROP2 antibody via a thioether bond (hereinafter referred to as "TROP2-ADC (1)"):

[0661] [Formula 24]

[0662]

[0663] Where A represents the linking position with the antibody. The DAR of TROP2-ADC (1) was 3.5 to 4.5.

Embodiment 3

[0664] Embodiment 3: the generation of compound (1)

[0665] According to the production methods described in International Publication No. WO 2014 / 057687 and International Publication No. 2015 / 115091, a compound represented by the following formula (hereinafter referred to as "compound (1)") was produced:

[0666] [Formula 25]

[0667] .

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PUM

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Abstract

A pharmaceutical composition characterized in that an antibody-drug conjugate, in which a drug linker represented by the formula (wherein A represents an antibody binding site) is bonded to an antibody via a thioether bond, is combined with a PARP inhibitor and administered, and / or a therapeutic method characterized in that the antibody-drug conjugate is combined with a PARP inhibitor and administered to an individual.

Description

technical field [0001] The present invention relates to pharmaceutical compositions wherein a particular antibody-drug conjugate and a PARP inhibitor are administered in combination; and / or methods of treatment wherein a particular antibody-drug conjugate and a PARP inhibitor are administered in combination to a subject. Background technique [0002] Single-strand breaks and double-strand breaks are known as types of DNA damage, each of which has a repair mechanism. If the type of DNA damage is a single strand break, it will be repaired by base excision repair primarily via PARP (poly[adenosine 5'-diphosphate (ADP)-ribose] polymerase) acting on it. If the type of DNA damage is a double-strand break, it will be repaired by homologous recombination repair mainly through BRCA, ATM, RAD51, etc. acting on it (Non-Patent Reference 1). [0003] PARP inhibitors are drugs that have the function of inhibiting PARP (particularly PARP-1 and PARP-2) and thus prevent single-strand break ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184A61K31/454A61K31/4745A61K31/502A61K31/5025A61K31/55A61K45/00A61P35/00A61P43/00C07K16/28A61K47/68C12N15/13
CPCA61K31/4184A61K31/454A61K31/502A61K31/5025A61K31/55A61P43/00A61P35/00C07K16/28C07K16/32A61K39/39558C07K16/30A61K47/6849A61K47/6851A61K47/6855A61K47/6889A61K45/06A61K47/68037A61K2300/00A61K47/6803A61K31/4745
Inventor 扇谷祐辅冈嶌大祐桥本悠里铃木宏和
Owner DAIICHI SANKYO CO LTD
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