Immune conjugate having dendron conjugated to antibody and use thereof
Inventors
Kim, Young Deug • PARK, Eun Ji • KIM, YEJIN • Shin, Young Kee • Choi, Jun Young
Assignees
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Publication Number
US-10576158-B2
Publication Date
2020-03-03
Expiration Date
Abstract
An immune conjugate according to the present invention provides a pharmaceutical composition, which can be used in the target-oriented drug treatment by conjugating a dendron allowing a plurality of drugs to be bound to a surface thereof and a target-directed antibody, and especially, can deliver high concentrations of drugs in a tumor-specific manner to exhibit a strong anticancer effect by conjugating a hydrophilic dendron, to which a plurality of anticancer drugs are bound, to an antibody.
Core Innovation
The invention provides an anti-cancer immunoconjugate comprising an antibody and a dendron. The dendron has a thiol group at its center and is conjugated to a cysteine residue present in a constant region or a variable region of a heavy or light chain of the antibody, and an anti-cancer drug is conjugated to the dendron.
A hydrophilic thiol-containing dendron is described, including a dendron obtained by reducing a cystamine-core PAMAM dendrimer to provide the thiol group at the dendron center. The dendron is conjugated to cysteine-engineered antibodies, including cysteine residue conjugation in constant or variable regions of heavy or light chains.
The disclosure addresses conventional antibody-drug conjugate limitations by configuring the immunoconjugate to support tumor-targeted delivery and high concentration of drugs at the tumor site. Linkers and drug conjugation approaches are described, including linker reactivity options and cis-aconityl-doxorubicin, with pH-dependent drug release described as lower at neutral blood conditions and elevated at acidic pH associated with lysosomes/endosomes.
Claims Coverage
The provided independent claim covers an immunoconjugate defined by the pairing of an antibody with a dendron that contains a thiol group at its center, where the dendron is conjugated to a cysteine residue in a heavy or light chain region of the antibody, and where an anti-cancer drug is conjugated to the dendron. The dependent claims further specify dendron preparation, dendrimer type, antibody selection, linker attachment, and pharmaceutical cancer-treatment composition/use.
Dendron-thiol-center immunoconjugate with cysteine-region antibody attachment
An immunoconjugate comprising an antibody and a dendron, wherein the dendron has a thiol group at its center, wherein the dendron is conjugated to the cysteine residue present in a constant region or a variable region of a heavy or light chain of the antibody, and wherein an anti-cancer drug is conjugated to the dendron.
Cystamine-core dendron generation by reduction
The dendron is made by reducing a cystamine-core dendrimer.
PAMAM dendrimer dendron
The dendrimer is a polyamidoamine (PAMAM) dendrimer.
Tumor-specific antibody selection
The antibody component is a tumor-specific antibody.
Antibody formats covered
The antibody is chosen from polyclonal, monoclonal, chimeric, humanized, or multiple antibody fragment formats including an Fv fragment, Fab fragment, or F(ab')2 fragment, or an scFv fragment.
Linker between dendron and antibody
The dendron is linked to the antibody through a linker.
Across the independent claim and its refinements, the central inventive concept is an antibody-dendron immunoconjugate built around a dendron with a thiol group at its center, conjugated to cysteine residues located in constant or variable regions of the antibody (heavy or light chains), with an anti-cancer drug conjugated to the dendron; dependent features further constrain dendron origin, dendrimer type, antibody selection/format, and optional linker connection.
Stated Advantages
Documented Applications
No documented applications found
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