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

Inventors

Ishizaki, Masayuki • Suzuki, Osamu • KYUTOKU, Mariko • YUKIURA, Hiroshi • HARA, KYOKO • CHIHARA, Masataka • OTSUKA, Takafumi • WADA, Teiji

Assignees

Daiichi Sankyo Co Ltd

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.

Core Innovation

The disclosure describes antibody-drug conjugates represented by formula (II) in which Ab is an anti-EGFR antibody or an antigen-binding fragment, optionally having a remodeled glycan. The linker L links Ab and D, and Ab is bound to L through the glycan or remodeled glycan of Ab. In the defined linker, L is represented as -Lb-La-Lp-Lc-*, where the asterisk represents bonding to the drug D.

The linker is further defined by Lp as -GGFG- or -GGPI-, La as a defined carbon-oxygen-carbon chain, Lb as a structural formula in which the asterisk bonds to La and the wavy line bonds to the glycan or remodeled glycan of Ab, and Lc as -NH-CH2-. The drug D is represented by a compound formula, and L bonds to any -NH2 or a hydroxy group included in L1, with L1 selected from enumerated formulas and Q, Q′, R21, R22, and W defined as stated in the claims.

The N297 glycan is represented with wavy-line bonding to Asn297, and L(PEG) is represented as —(CH2—CH2O)n5—CH2—CH2—NH—. The amino group at the right end of 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 branched β-Man chains, and the asterisk represents bonding to a nitrogen atom at 1- or 3-position on a 1,2,3-triazole ring. The antibody component is also constrained in some variants by explicit SEQ ID NO-based light-chain and heavy-chain sequences, variable-region residue ranges, or CDR sequence sets.

In further embodiments, the conjugates include quantitative drug-loading constraints and specific N297 glycan variants such as N297-(Fuc)MSG1 or N297-(Fuc)SG. The disclosed conjugates define particular variants of Ab–L–D for systemic delivery of a cyclic dinucleotide STING agonist moiety.

Claims Coverage

The independent claims center on antibody-drug conjugates represented by formulae in which an anti-EGFR antibody, optionally with remodeled glycan, is linked to a drug through a glycan-mediated linker architecture. Across the independent claim sets, the inventive features repeatedly include the structured linker L (-Lb-La-Lp-Lc-*), defined drug D formula options, N297 glycan bonding to Asn297 with L(PEG) and triazole nitrogen linkage, and SEQ ID NO-defined antibody selections.

Across the independent claims, the inventive coverage centers on antibody-drug conjugates with a structured glycan-mediated linker, defined drug formula options, and antibody selection limits based on SEQ ID NOs or CDR sequence sets. The recurring core features are the Ab–L–D framework, Lb-La-Lp-Lc-* linker architecture, N297 glycan bonding to Asn297 with L(PEG) amide linkage and triazole nitrogen bonding, and additional variants including anti-EGFR antibodies, N297-(Fuc)MSG1 or N297-(Fuc)SG, and m1 loading constraints.

Stated Advantages

Documented Applications