Non-natural amatoxin-type antibody conjugate
Inventors
Zhu, Yi • Li, Jie • YU, Yongguo • LIU, Weijia • Zhuo, Shi
Assignees
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Publication Number
US-12268752-B2
Publication Date
2025-04-08
Expiration Date
Abstract
Disclosed is a non-natural amatoxin-type antibody conjugate, said conjugate similar to the natural amatoxin is linked to a biopharmaceutically acceptable salt with a target biomolecule so as to obtain stability in blood plasma, and efficiently kill tumor cells in cells.
Core Innovation
The invention relates to a non-natural amatoxin-antibody conjugate comprising a toxin moiety having a structural formula (I), or a pharmaceutically acceptable salt thereof, and a biomacromolecule moiety A having a binding affinity to a target. The toxin moiety includes variable substituents defined by R1, R2, R3, R4, and R5, with substituent forms including hydrogen, hydroxyl, oxygen-linked L-amino groups, and OC1-6 alkyl.
The conjugate includes a plasma-stable linker L that connects the toxin moiety to A, where L is defined as a multicomponent structure L1-[L2]m-[AA]n-L3. In this architecture, L1 is a linker for connecting to A, L2 is a spacer connecting L1 to AA, m is an integer selected from 1-6, AA is a structural fragment consisting of 1 to 6 amino acids with n being 0 or 1, and L3 is a structural fragment connecting to the toxin moiety.
The invention specifies that moiety A can be a pharmaceutically acceptable biomacromolecule format, including antibody formats such as chimeric, deimmunized, humanized, human, bispecific/tetra-specific antibodies, and nanobodies, as well as antigen-binding fragments and related formats. The conjugate concept is framed for drug/pharmaceutical compositions and for anti-cancer use against various malignant tumors.
Claims Coverage
The independent claim family covers one non-natural amatoxin-antibody conjugate with three inventive features: a structurally defined amatoxin toxin moiety, a target-binding biomacromolecule moiety A, and a defined multicomponent linker L.
Structurally defined non-natural amatoxin toxin moiety with variable substituents
A toxin moiety having a structural formula (I) or a pharmaceutically acceptable salt thereof, with R1-R5 substituents defined as R1 being H, —OH, or —O-L-A; R2 being H or —OH; R3 being OC1-6 alkyl; R4 being H or -L-A-NH2 or —OH; and R5 being —NH2, —OH, —NH-L-A or —O-L-A.
Target-binding biomacromolecule moiety connected through a multicomponent linker
A biomacromolecule moiety A having a binding affinity to a target, wherein L is a linker comprising L1-[L2]m-[AA]n-L3, with L1 selected as a linker for connecting to A, L2 as a spacer connecting L1 to AA, m an integer selected from 1-6, L3 as a structural fragment connecting to the toxin moiety, and AA as a structural fragment consisting of 1 to 6 amino acids with n being 0 or 1.
The claims center on a conjugate combining a defined amatoxin toxin moiety with a target-binding biomacromolecule moiety A via the specified linker architecture L = L1-[L2]m-[AA]n-L3.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Anti-cancer use against various malignant tumors.
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