Antibody-pyrrolobenzodiazepine derivative conjugate which binds caludin-6 and claudin-9
Inventors
Toda, Narihiro • Ota, Yusuke • DOI, Fuminao • Meguro, Masaki • Hayakawa, Ichiro • Ashida, Shinji • Masuda, Takeshi • Nakada, Takashi • Iwamoto, Mitsuhiro • HARADA, Naoya • TERAUCHI, Tomoko • Okajima, Daisuke • Nakamura, Kensuke • Uchida, Hiroaki • Hamada, Hirofumi
Assignees
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Publication Number
US-12606634-B2
Publication Date
2026-04-21
Expiration Date
Abstract
The present invention provides a novel antibody-pyrrolodiazepine derivative and a novel antibody-pyrrolodiazepine derivative conjugate using the same, and a novel CLDN6 and/or CLDN9 antibody.
Core Innovation
The invention relates to an antibody-drug conjugate selected from a group of antibody-drug conjugates, in which the antibody Ab comprises a heavy chain and a light chain specified by complementarity determining regions represented by SEQ ID NO: 9, 10, and 11, and SEQ ID NO: 5, 6, and 7, or by heavy-chain and light-chain amino acid residue ranges from specified SEQ ID NOs. The N297 glycan of Ab is defined as N297-(Fuc)MSG1 having a structure in which each wavy line represents bonding to Asn297 of the antibody.
In the N297-(Fuc)MSG1 structure, L(PEG) is represented as —NH—CH2CH2(O—CH2CH2)3—*, and the amino group at the left end is bound via an amide bond to a carboxylic acid at the 2-position of a sialic acid at the non-reducing terminal in the 1-3 branched chains of β-Man in the N297 glycan. Each asterisk represents bonding to a nitrogen atom at the 1- or 3-position of the triazole ring in the corresponding structural formula.
The independent claims further select conjugates in which m2 represents an integer of 1. Dependent refinements include additional antibody sequence constraints, specified residue endpoints, and enumerated antibody modification categories, including N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue at an N terminus, and amidation of a proline residue.
Claims Coverage
The provided independent claims define an antibody-drug conjugate by antibody CDR sequences or heavy/light residue ranges, together with a required N297-(Fuc)MSG1 glycan structure linked through L(PEG) to a triazole ring. The claims repeatedly include m2 representing an integer of 1.
Antibody-drug conjugate defined by CDR sequences and N297-(Fuc)MSG1 glycan
An antibody-drug conjugate in which Ab comprises a heavy chain with CDRH1, CDRH2, and CDRH3 represented by SEQ ID NO: 9, 10, and 11, and a light chain with CDRL1, CDRL2, and CDRL3 represented by SEQ ID NO: 5, 6, and 7; and wherein N297 glycan represents N297-(Fuc)MSG1 having a structure in which each wavy line represents bonding to Asn297 and L(PEG) is represented as —NH—CH2CH2(O—CH2CH2)3—* with the amino group bound via an amide bond to a carboxylic acid at the 2-position of a sialic acid and each asterisk representing bonding to a nitrogen atom at the 1- or 3-position of the triazole ring.
Antibody-drug conjugate defined by heavy/light residue ranges and N297-(Fuc)MSG1 glycan
An antibody-drug conjugate in which Ab comprises a heavy chain comprising amino acid residues 20 to 469 of SEQ ID NO: 52 or SEQ ID NO: 56 and a light chain comprising amino acid residues 21 to 234 of SEQ ID NO: 36, SEQ ID NO: 40, or SEQ ID NO: 44; and wherein N297 glycan represents N297-(Fuc)MSG1 having a structure in which each wavy line represents bonding to Asn297 and L(PEG) is represented as —NH—CH2CH2(O—CH2CH2)3—* with the amino group bound via an amide bond to a carboxylic acid at the 2-position of a sialic acid and each asterisk representing bonding to a nitrogen atom at the 1- or 3-position of the triazole ring.
m2 equals an integer of 1
The independent claims require m2 to represent an integer of 1 in the selected group.
Antibody modifications and structural refinements
Dependent claim refinements include additional antibody modification categories, possible two-heavy-chain architecture, tighter heavy-chain residue endpoints in some embodiments, and amidation of a proline residue at the heavy-chain carboxyl terminus.
Across the independent claims, the claim scope is defined by an antibody-drug conjugate in which the antibody is constrained by specified CDR sequences or heavy/light chain residue ranges, and the N297 glycan is N297-(Fuc)MSG1 with bonding to Asn297 and an L(PEG) moiety linked to a triazole ring. Dependent refinements add antibody modification types and structural options such as two heavy chains and proline amidation.
Stated Advantages
In vivo antitumor efficacy in nude mouse xenograft models showing tumor regression for ADC49/ADC54/ADC55 with no weight loss.
In vitro anticellular activity against HER2-positive and control antigen-negative cell lines.
Documented Applications
In vivo antitumor efficacy in nude mouse xenograft models.
In vitro anticellular activity against HER2-positive and control antigen-negative cell lines.
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