Cyclic dinucleotide derivative based antibody-drug conjugates
Inventors
Tsuda, Toshifumi • TABUCHI, TOSHIKI • Watanabe, Hideaki • Kobayashi, Hiroyuki • Ishizaki, Masayuki • HARA, KYOKO • WADA, Teiji • Arai, Masami
Assignees
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Publication Number
US-12370263-B2
Publication Date
2025-07-29
Expiration Date
Abstract
Desired is development of novel CDN derivatives having STING agonist activity; and a therapeutic agents and/or therapeutic methods using the novel CDN derivatives for diseases associated with STING agonist activity. Further desired is development of a therapeutic agents and/or therapeutic methods capable of delivering the novel CDN derivatives specifically to targeted cells and organs for diseases associated with STING agonist activity. The present invention provides novel CDN derivatives having potent STING agonist activity, and antibody-CDN derivative conjugates including the novel CDN derivatives.
Core Innovation
The invention relates to an antibody-drug conjugate represented by formula (II), in which an antibody or an antigen-binding fragment is linked to a drug moiety D through a linker L represented by -Lb-La-Lp-Lc-*, where the asterisk indicates bonding to D. The antibody is optionally glycan-remodeled and is not an anti-EGFR antibody or antigen-binding fragment, an anti-TROP2 antibody or antigen-binding fragment, or an anti-CD70 antibody or antigen-binding fragment. The conjugate includes m1 in the range of 1 to 10.
The linker contains a peptide Lp consisting of two to four amino acids, a defined La segment selected from specified carbonyl-containing structures with integer constraints on n2, n3, n4, and n9, and an Lb spacer bonding La to a glycan or remodeled glycan of Ab or to a cysteine residue of Ab. Lc is selected from specified -NH-CH2- and related aryl or heteroaryl-containing groups or is absent, and Ab bonds directly from an amino acid residue of Ab to L or optionally via a glycan or remodeled glycan of Ab to L.
The drug moiety D is represented by formula (I) and includes constrained structural variables, including L bonding to any -NH2 or hydroxy group included in L1, L1 selected from specified formula groups with optional substitution, and variable definitions for Q1/Q1’, Q2/Q2’, W1, W2, R1-R5, Z1-Z3, Z4, and Z5. The disclosed work also includes phosphorus-containing, CDN-derived drug-linker constructs and describes STING agonist activity, anti-tumor activity, and the liberation of D upon cleavage in target cells.
The document further identifies multi-step synthesis, characterization by MS and NMR, and antibody-CDN conjugate examples including anti-HER2 antibody 2-CDN conjugates and other antibody-drug conjugation configurations.
Claims Coverage
The consolidated claim coverage centers on one independent claim: an antibody-drug conjugate of formula (II) with a constrained linker architecture, a constrained drug moiety D of formula (I), excluded antibody targets, and m1 in the range of 1 to 10. The inventive features below merge the overlapping structural constraints repeated across the provided items.
Antibody-drug conjugate of formula (ii) with excluded antibody targets
An antibody-drug conjugate represented by formula (II) wherein Ab is an antibody or an antigen-binding fragment of the antibody, where a glycan of the antibody is optionally remodeled, and wherein the antibody or the antigen-binding fragment is not an anti-EGFR antibody or antigen-binding fragment, an anti-TROP2 antibody or antigen-binding fragment, or an anti-CD70 antibody or antigen-binding fragment.
Linker architecture -Lb-La-Lp-Lc-* with defined peptide and spacer features
L represents a linker linking Ab and D and is represented by -Lb-La-Lp-Lc-*, wherein the asterisk indicates bonding to D; Lp is a peptide that consists of two to four amino acids; La is selected from the specified carbonyl-containing group patterns with integer constraints on n2, n3, n4, and n9; Lb represents a spacer bonding La and a glycan or remodeled glycan of Ab or a spacer bonding La and a cysteine residue of Ab; Lc represents -NH-CH2-, -NH-phenyl group-CH2-O(C=O)-, -NH-heteroaryl group-CH2-O(C=O)-, or is absent; and Ab bonds directly from an amino acid residue of Ab to L or optionally bonds via a glycan or remodeled glycan of Ab to L.
Drug moiety d represented by formula (i) with constrained attachment and variable groups
D represents a compound represented by formula (I), wherein L bonds to any -NH2 or hydroxy group included in L1; L1 is selected from the defined formulas and is optionally substituted with one to three groups selected from a hydroxy group, -NH2, a 2-hydroxyacetylaminomethyl group, and a 2-[(2-hydroxyacetyl)amino]ethyl group; and the claim defines Q1/Q1’, Q2/Q2’, W1, W2, R1-R5, Z1-Z3, Z4, and Z5 as specified variable selections.
Conjugate loading parameter m1 in the range of 1 to 10
The conjugate of formula (II) specifies m1 as an integer in the range of 1 to 10.
The consolidated claim scope is a single antibody-drug conjugate of formula (II) that couples a restricted antibody or antigen-binding fragment to a formula (I) drug through the defined -Lb-La-Lp-Lc-* linker, with m1 limited to 1 to 10 and multiple structural variables constrained as recited in the claim.
Stated Advantages
Potent STING agonism and anti-tumor effects.
The drug D can be liberated upon cleavage in target cells.
Preferably yields anti-tumor activity.
Documented Applications
Use of antibody-drug conjugates for cancers or conditions associated with STING agonist activity.
Evaluation of human STING agonist activity using THP1-Dual IRF3 reporter EC50 values and binding activity to the STING C-terminal domain via protein thermal shift assay (ΔTm).
Anti-tumor efficacy testing in multiple mouse xenograft/transplant models using antibody-CDN conjugates, including assessments involving antibody-target dependence and linker/drug-conjugation comparisons.
Systemic delivery to antigen-expressing tumors using the described antibody-drug conjugate construct.
Use as phosphorus-based Drug-Linker compounds or intermediates featuring a thiol/disulfide-functionalized phosphorylated scaffold with peptide/amide payload fragments, including characterization by MS and 1H/31P NMR.
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