US 12,678,512 B2 · Anti-EGFR antibody-drug conjugate with a cyclic dinucleotide derivative

Abstract

[Problem] It is desired to develop an antibody-drug conjugate capable of being systemically administered and delivering a STING agonist specifically to a target cells or organ (for example, a tumor lesion), and a therapeutic agent and/or therapeutic method using the antibody-drug conjugate for diseases related to STING agonist activity, for example, diseases (for example, cancers) to which immunostimulation therapy can be applied. [Solution] The present invention provides a novel antibody-CDN derivative conjugate which can be systemically administered and exhibits an antitumor effect against an antigen-expressing tumor.

Claims49

Dependent claims

An antibody-drug conjugate represented by the following formula (II):

wherein m1 ranges from 1 to 10;
Ab represents an antibody or an antigen-binding fragment of the antibody, wherein the antibody optionally has a remodeled glycan,
wherein the antibody is an anti-EGFR antibody;
L represents a linker linking Ab and D, wherein
Ab is bound to L through the glycan or remodeled glycan of Ab, and
L is represented by -Lb-La-Lp-Lc-*
wherein the asterisk represents bonding to the drug D;
Lp is -GGFG- or -GGPI-:
La represents —C(═O)—CH2CH2—C(═O)—;
Lb represents the following formula:
wherein, in the structural formula of Lb shown above, the asterisk represents bonding to La, and the wavy line represents bonding to the glycan or remodeled glycan of Ab;
and
Lc represents —NH—CH2—;
D represents a compound represented by the following formula (1):
wherein
L bonds to any —NH2 or a hydroxy group included in L1,
L1 represents any one group of the formulas selected from the group consisting of:
wherein the wavy line represents a position of substitution,
Q and Q′ each independently represent a hydroxy group or a thiol group,
R21 and R22 each independently represent a hydroxy group or a fluorine atom, and
W represents —NH— or a sulfur atom.

18 more elements

An antibody-drug conjugate represented by the following formula:

wherein Ab represents any one selected from the group consisting of the following:
an antibody comprising a light chain comprising a light chain variable region comprising of amino acid residues 1 to 108 of SEQ ID NO:
9 and a heavy chain comprising a heavy chain variable region comprising amino acid residues 1 to 119 of SEQ ID NO:
10, and
an antibody comprising a light chain comprising a light chain variable region comprising amino acid residues 1 to 108 of SEQ ID NO:
11 and a heavy chain comprising a heavy chain variable region comprising amino acid residues 1 to 116 of SEQ ID NO:
12,
wherein N297 glycan of Ab is represented by the following formula:
wherein the wavy line represents bonding to Asn297 of the antibody,
L(PEG) represents —(CH2—CH2—O)n5—CH2—CH2—NH—,
wherein the amino groups at the right end of the L(PEG) is bound via an amide bond to a carboxyl group at the 2-position on a sialic acid at the non-reducing terminal on each of 1-3 and 1-6 branched chains of β-Man in the N297 glycan,
the asterisk represents bonding to a nitrogen atom at 1- or 3-position on the 1,2,3-triazole ring,
n5 is 3, and
m2 is 2.

11 more elements

An antibody-drug conjugate represented by the following formula:

wherein Ab represents any one selected from the group consisting of the following:
an antibody comprising a light chain comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:
59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:
60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO:
61 and a heavy chain comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:
62, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:
63, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:
64, and
an antibody comprising a light chain comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:
65, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:
66, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO:
67 and a heavy chain comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:
68, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:
69, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:
70, wherein N297 glycan of Ab is represented by the following formula:
wherein the wavy line represents bonding to Asn297 of the antibody,
L(PEG) represents —(CH2—CH2—O)n5—CH2—CH2—NH—,
wherein the amino groups at the right end of the L(PEG) is bound via an amide bond to a carboxyl group at the 2-position on a sialic acid at the non-reducing terminal on each of 1-3 and 1-6 branched chains of β-Man in the N297 glycan,
the asterisk represents bonding to a nitrogen atom at 1- or 3-position on the 1,2,3-triazole ring,
n5 is 3, and
m2 is 2.

18 more elements

An antibody-drug conjugate represented by the following formula:

wherein Ab represents any one selected from the group consisting of the following:
an antibody comprising a light chain comprising a light chain variable region comprising amino acid residues 1 to 108 of SEQ ID NO:
9 and a heavy chain comprising a heavy chain variable region comprising amino acid residues 1 to 119 of SEQ ID NO:
10, and
an antibody comprising a light chain comprising a light chain variable region comprising amino acid residues 1 to 108 of SEQ ID NO:
11 and a heavy chain comprising a heavy chain variable region comprising amino acid residues 1 to 116 of SEQ ID NO:
12,
wherein N297 glycan is represented by the following formula:
wherein the wavy line represents bonding to Asn297 of the antibody,
L(PEG) represents —(CH2—CH2—O)n5—CH2—CH2—NH—,
wherein the amino group at the right end of the L(PEG) is bound via an amide bond to a carboxyl group at the 2-position on a sialic acid at the non-reducing terminal of a 1-3 branched chain of β-Man in the N297 glycan,
the asterisk represents bonding to a nitrogen atom at 1- or 3-position on the 1,2,3-triazole ring, and
n5 is 3, and
m2 is 1.

11 more elements

An antibody-drug conjugate represented by the following formula:

wherein Ab represents any one selected from the group consisting of the following:
an antibody comprising a light chain comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:
59, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:
60, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO:
61 and a heavy chain comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:
62, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:
63, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:
64, and
an antibody comprising a light chain comprising a CDRL1 comprising the amino acid sequence set forth in SEQ ID NO:
65, a CDRL2 comprising the amino acid sequence set forth in SEQ ID NO:
66, and a CDRL3 comprising the amino acid sequence set forth in SEQ ID NO:
67 and a heavy chain comprising a CDRH1 comprising the amino acid sequence set forth in SEQ ID NO:
68, a CDRH2 comprising the amino acid sequence set forth in SEQ ID NO:
69, and a CDRH3 comprising the amino acid sequence set forth in SEQ ID NO:
70,
wherein N297 glycan is represented by the following formula:
wherein the wavy line represents bonding to Asn297 of the antibody,
L(PEG) represents —(CH2—CH2—O)n5—CH2—CH2—NH—,
wherein the amino group at the right end of the L(PEG) is bound via an amide bond to a carboxyl group at the 2-position on a sialic acid at the non-reducing terminal of a 1-3 branched chain of β-Man in the N297 glycan,
the asterisk represents bonding to a nitrogen atom at 1- or 3-position on the 1,2,3-triazole ring, and
n5 is 3, and
m2 is 1.

19 more elements

Dependencies are inferred from the claim text.

Anti-EGFR antibody-drug conjugate with a cyclic dinucleotide derivative

Life of this patent

Anti-EGFR antibody-drug conjugate with a cyclic dinucleotide derivative

Life of this patent

Abstract

Claims49