Compound for preparation of antibody-payload conjugate and use thereof
Inventors
Kim, Ju Hwan • Lee, Tae Jin • Chung, Sang Jeon • LEE, Young Geun • Seo, Jin Woo
Assignees
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Publication Number
US-12296019-B2
Publication Date
2025-05-13
Expiration Date
Abstract
The present application relates to a novel linker for use in bioconjugation, comprising two or more electrophilic carbon atoms of a carbonyl group, and a click chemistry functional group and, more specifically, to a linker through which a compound, a peptide, and/or a protein can be directly and/or indirectly linked by a substitution reaction to a desired target molecule, that is, a target molecule.
Core Innovation
The invention relates to an antibody-payload conjugate in which an antibody (Ab) is linked to an active moiety (Am) that comprises a drug molecule. The conjugate includes a linker (B) formed by a click chemistry reaction between a first click chemistry functional group and a second click chemistry functional group, and the first and second click chemistry functional groups are independently selected from acetylene, transcyclooctene, cyclooctyne, dyarylcyclooctyne, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctyne.
The conjugate further uses an Fc binding peptide (Fp) represented by DCAWHXGELVWCT (SEQ ID NO: 1), where D, C, A, W, H, X, G, E, L, V, and T are defined residues and X is selected from 2,3-Diaminopropionic Acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), or lysine (Lys). The Fc binding peptide is linked to the antibody through amino acid residue 6 of the Fc binding peptide, and the nitrogen atom linked to the Ab is derived from lysine 246 or lysine 248 of the Fc region of the antibody.
The conjugate includes additional structural constraints for the linker/adaptor architecture. The cysteine at the N-terminal and the cysteine at the C-terminal are optionally linked by a disulfide bond, n is an integer of 1 to 2, and R3′ is C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or C1-6 heteroalkylene including at least one selected from N, O, and S.
Claims Coverage
The claims coverage centers on one independent antibody-payload conjugate claim with a defined Fc binding peptide sequence and a click chemistry-formed linker. The inventive features combine the Ab-Am conjugate framework, the specific Fc binding peptide sequence and attachment logic, and the selectable click chemistry pair used to form linker B, along with linker length and backbone constraints.
Antibody-payload conjugate with drug-containing active moiety
An antibody-payload conjugate in which Ab is an antibody, and Am is an active moiety or a structure including the active moiety, wherein the active moiety comprises a drug molecule.
Fc binding peptide sequence linked via amino acid residue 6
Fp comprises a Fc binding peptide represented by DCAWHXGELVWCT (SEQ ID NO: 1), with the Fc binding peptide linked to the antibody through amino acid residue 6 of the Fc binding peptide.
Click chemistry-formed linker between independently selected functional groups
B is formed by a click chemistry reaction of a first click chemistry functional group and a second click chemistry functional group, wherein the first and second click chemistry functional groups are independently selected from acetylene, transcyclooctene, cyclooctyne, dyarylcyclooctyne, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctyne, which can be reacted with each other.
Attachment to Fc-region lysine-derived nitrogen
Y4 is NH derived from amino acid residue 6 of the Fc binding peptide, wherein the amino acid residue 6 is X, and wherein the nitrogen atom linked to the Ab is derived from lysine 246 or lysine 248 of the Fc region of the antibody.
Linker length and heteroalkylene definition
n is an integer of 1 to 2, and R3′ is C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or C1-6 heteroalkylene, wherein the heteroalkylene includes at least one selected from N, O, and S.
Optional disulfide bond between terminal cysteines
The cysteine at N-terminal and the cysteine at C-terminal are optionally linked to each other by a disulfide bond.
Overall, the claims define an antibody-payload conjugate with a drug-containing active moiety, a click-chemistry-formed linker B, and the Fc binding peptide DCAWHXGELVWCT (SEQ ID NO: 1) attached through residue 6 with antibody attachment linked to lysine 246 or lysine 248 of the Fc region, together with specified linker and disulfide-bond constraints.
Stated Advantages
Site-specific payload linking via the defined Fc-binding peptide and the antibody attachment derived from lysine 246 or lysine 248.
Maintained or altered biological activity depending on cis vs trans linker variant.
Improved uniformity from uniform binding positions.
Enables detection/diagnosis/biomarkers and anticancer therapy.
Documented Applications
Detection/diagnosis and biomarkers using the disclosed antibody-payload conjugates.
Anticancer therapy, including breast cancer, using an antibody-payload conjugate payload comprising a drug molecule.
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