Antibody-drug complex containing toll-like receptor 7/8 dual agonist compound

Patent metadata

Field	Value
Publication number	US-12390536-B2
Application number	US-202418896098-A
Country	US
Kind code	B2
Filing date	Sep 25, 2024
Priority date	Oct 31, 2022
Publication date	Aug 19, 2025
Grant date	Aug 19, 2025

Abstract

An antibody-drug conjugate of formula (I) or salt thereof of formula I:

may have Ab as an anti-CLDN6 antibody or an antigen-binding fragment thereof. The antibody-drug conjugate of formula (I) may be (a) an antibody-drug conjugate comprising Ab bound to 1-{3-[(3S)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione, (b) an antibody-drug conjugate comprising Ab bound to {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methyl[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]carbamate, (c) an antibody-drug conjugate comprising Ab bound to N-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-N-cyclopropyl-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide, or (d) an antibody-drug conjugate comprising Ab bound to 1-{3-[(3R)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione.

First claim

The invention claimed is:

1. An antibody-drug conjugate of formula (I) or salt thereof:
(D L -) n -Ab  (I),

wherein
D L is a drug-linker of the antibody-drug conjugate,
Ab is an anti-CLDN6 antibody or an antigen-binding fragment thereof, and
n is in a range of from 1 to 16, and
wherein the antibody-drug conjugate of formula (I) is selected from the group consisting of
an antibody-drug conjugate consisting of Ab bound to 1-{3-[(3S)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione,
an antibody-drug conjugate consisting of Ab bound to {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methyl[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]carbamate,
an antibody-drug conjugate consisting of Ab bound to N-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-N-cyclopropyl-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide, and
an antibody-drug conjugate consisting of Ab bound to 1-{3-[(3R)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione.

2. The antibody-drug conjugate or salt of claim 1 , wherein Ab is an anti-CLDN6 antibody or an antigen-binding fragment thereof selected from the group consisting of Ab-A and Ab-B,
wherein Ab-A is an anti-CLDN6 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising CDR1 consisting of amino acid sequence of amino acid Nos. 31 to 35 of SEQ ID NO: 2, CDR2 consisting of the amino acid sequence of amino acid Nos. 50 to 65 of SEQ ID NO: 2, and CDR3 consisting of the amino acid sequence of amino acid Nos. 95 to 102 of SEQ ID NO: 2; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid Nos. 24 to 34 of SEQ ID NO: 4, CDR2 consisting of the amino acid sequence of amino acid Nos. 50 to 56 of SEQ ID NO: 4, and CDR3 consisting of the amino acid sequence of amino acid Nos. 89 to 97 of SEQ ID NO: 4, and
wherein Ab-B is an anti-CLDN6 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid Nos. 31 to 35 of SEQ ID NO: 6, CDR2 consisting of the amino acid sequence of amino acid Nos. 50 to 65 of SEQ ID NO: 6, and CDR3 consisting of the amino acid sequence of amino acid Nos. 95 to 102 of SEQ ID NO: 6; and a light chain variable region comprising CDR1 consisting of the amino acid sequence of amino acid Nos. 24 to 34 of SEQ ID NO: 8, CDR2 consisting of the amino acid sequence of amino acid Nos. 50 to 56 of SEQ ID NO: 8, and CDR3 consisting of the amino acid sequence of amino acid Nos. 89 to 97 of SEQ ID NO: 8.

3. The antibody-drug conjugate or salt of claim 1 , wherein Ab is an anti-CLDN6 antibody or an antigen-binding fragment thereof selected from the group consisting of Ab-C and Ab-D,
wherein Ab-C is an anti-CLDN6 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid Nos. 1 to 117 of SEQ ID NO: 2 and a light chain variable region consisting of the amino acid sequence of the amino acid Nos. 1 to 108 of SEQ ID NO: 4, and
wherein Ab-D is an anti-CLDN6 antibody or an antigen-binding fragment thereof comprising a heavy chain variable region consisting of the amino acid sequence of amino acid Nos. 1 to 117 of SEQ ID NO: 6 and a light chain variable region consisting of the amino acid sequence of amino acid Nos. 1 to 108 of SEQ ID NO: 8.

4. The antibody-drug conjugate or salt of claim 2 , wherein Ab is Ab1 or Ab2, and
wherein Ab1 is an anti-CLDN6 antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 2 and a light chain consisting of the amino acid sequence of SEQ ID NO: 4, and
wherein Ab2 is an anti-CLDN6 antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 6 and a light chain consisting of the amino acid sequence of SEQ ID NO: 8.

5. The antibody-drug conjugate or salt of claim 1 , wherein Ab is Ab1 or Ab2,
wherein the antibody-drug conjugate is selected from the group consisting of
an antibody-drug conjugate consisting of Ab1 bound to 1-{3-[(3S)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione,
an antibody-drug conjugate consisting of Ab2 bound to 1-{3-[(3S)-4-[(4-{([2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione,
an antibody-drug conjugate consisting of Ab1 bound to {(2S)-1-[(4-{[2-amino-7-chloro-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]pyrrolidin-2-yl}methyl[2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl]carbamate,
an antibody-drug conjugate consisting of Ab1 bound to N-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-N-cyclopropyl-3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide, and
an antibody-drug conjugate consisting of Ab1 bound to 1-{3-[(3R)-4-[(4-{[2-amino-4-(pentylamino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}-3-methoxyphenyl)methyl]-3-(fluoromethyl)piperazin-1-yl]-3-oxopropyl}-1H-pyrrole-2,5-dione, and
wherein Ab1 is an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 2 and a light chain consisting of the amino acid sequence of SEQ ID NO: 4,
Ab2 is an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 6 and a light chain consisting of the amino acid sequence of SEQ ID NO: 8.

6. The antibody-drug conjugate or salt of claim 1 , wherein the antibody-drug conjugate is

and
Ab1 is an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 2 and a light chain consisting of the amino acid sequence of SEQ ID NO: 4,
Ab2 is an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 6 and a light chain consisting of the amino acid sequence of SEQ ID NO: 8, and
n is 1 to 16.

7. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

8. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

9. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

10. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

11. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

12. The antibody-drug conjugate or salt of claim 6 , wherein the antibody-drug conjugate is

and
wherein n is in a range of from 1 to 8.

13. A pharmaceutical composition,

Assignees

• Astellas Pharma Inc

Inventors

• Akaiwa Michinori
• Seki Yohei
• Wang Yinghua
• Miguelez Javier Ramos
• Ohnuki Kei
• Kamikubo Takashi
• Asano Toru
• Kamikawa Akio
• Chaen Takashi
• Hoshi Rika
• Soga Shinji
• Kwon Chulwon

Classifications

• A61K47/6849 Primary

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

• A61K47/6889

  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

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• C07K16/00

  Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies · CPC title