Site-specific antibody conjugation and antibody-drug conjugate as specific embodiment thereof
Inventors
Chung, Sang Jeon • Kim, Ju Hwan • LEE, Young Geun • Lee, Tae Jin • Seo, Jin Woo
Assignees
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Publication Number
US-11896675-B2
Publication Date
2024-02-13
Expiration Date
Abstract
The present invention relates to technology capable of labeling a certain site of an antibody with a certain number of chemical functional groups or cargo moieties. The present invention may provide an antibody product having high uniformity. The present invention may provide an antibody product whose antibody functions are not degraded. That is, the present invention may provide an antibody product whose antibody binding affinity and half-life are not degraded. The present invention is of great significance as being the first technology allowing site-specific labeling of an antibody without any complicated processes.
Core Innovation
The invention relates to a modified antibody or its fragment comprising a bio-orthogonal click chemistry functional group. The modified antibody comprises one or more modified heavy chains, and each modified heavy chain comprises a modified lysine residue at the 248 position of the heavy chain amino acid sequence as determined by an EU numbering system. The modified lysine residue comprises a bio-orthogonal click chemistry functional group at the terminal end and does not comprise a terminal bio-reactive functional group selected from terminal hydroxy group, terminal carboxyl group, terminal thiol group, terminal amino group, or terminal aldehyde group.
The disclosure further defines the modified lysine by structural/formula descriptions in which H1 is a bio-orthogonal click chemistry functional group and D1 is a bond or a linker group. The linker portion includes alkylene, alkenylene, alkynylene, cycloalkylene, and repeating —[CH2]a—O—[CH2]b— segments, and the bio-orthogonal click chemistry functional group includes azide, tetrazine, dibenzocyclooctyne, and norbornene.
The described approach includes linker and site-specific antibody interactome constructs, engineered SSAI constructs, antibody conjugates, and antibody-payload conjugate frameworks based on click-chemistry complementarity. The disclosure also describes Fc lysine site transfer at Lys 246 and Lys 248, preparation of R1′-antibodies, and kits/methods for preparing SSAI constructs and associated conjugates.
Claims Coverage
The claim coverage centers on a modified antibody or fragment with bio-orthogonal click chemistry functionality installed on modified heavy-chain lysine at EU-defined position 248, with explicit exclusion of selected terminal bio-reactive groups. Across the provided items, the recurring inventive features are the site-specific heavy-chain lysine modification, the terminal click chemistry functional group with prohibited terminal groups, and related structural or linker definitions; related items also mention Fc lysines 246 and 248 in antibody conjugate and preparation contexts.
Heavy-chain lysine 248 site-specific modification
A modified antibody or its fragment comprising one or more modified heavy chain, wherein each modified heavy chain comprises a modified lysine residue at 248 position of heavy chain amino acid sequence, as determined by an EU numbering system.
Terminal bio-orthogonal click chemistry functional group on modified lysine
The modified lysine residue comprises a bio-orthogonal click chemistry functional group at a terminal end.
Exclusion of terminal bio-reactive functional groups on modified lysine
The modified lysine residue does not comprise a terminal bio-reactive functional group selected from terminal hydroxy group, terminal carboxyl group, terminal thiol group, terminal amino group, and terminal aldehyde group.
Selected bio-orthogonal click chemistry functional group options
The bio-orthogonal click chemistry functional group is one of azide, tetrazine, dibenzocyclooctyne, or norbornene.
Structural/formula definition of the modified lysine and linker portion
The modified lysine residue is defined by a structural formula in which H1 is a bio-orthogonal click chemistry functional group and D1 is a bond or selected linker groups, including alkylene, alkenylene, alkynylene, and cycloalkylene linker classes, with repeating —[CH2]a—O—[CH2]b— segment constraints.
Fc lysine 246 and 248 conjugate context
The document also refers to antibody conjugates and preparation of R1′-antibodies with first chemical functional groups site-specifically transferred to Fc lysines 246 and/or 248.
Overall, the claim coverage is directed to Fc/heavy-chain lysine 248 site-specific modification with a terminal bio-orthogonal click chemistry functional group and explicit exclusion of specified terminal bio-reactive groups, with dependent or related features further defining the click chemistry options, linker structure, and antibody conjugate context.
Stated Advantages
Improved yield/uniformity.
Preserving FcRn binding without half-life reduction.
SSAI leaving during conjugation.
Minimizing side reactions due to lack of highly bioreactive groups.
Purity >95% is reported for Compound I-SSFI (Lys).
Yield of 71% is reported for Compound I-SSFI (Lys).
Measured molecular weights are reported for the synthesized intermediates and peptides.
Highly uniform, non-degraded antibody binding/half-life products.
Uniform site-specific labeling without complicated processes.
Documented Applications
Antibody conjugates and antibody-payload conjugates based on click-chemistry complementarity, including frameworks using Cm-H2 and Cm-Ab.
Drug moiety conjugation is disclosed, with drug moiety examples including DM1, DM3, and DM4 and many cytotoxics [procedural detail omitted for safety].
Preparation of R1′-antibodies with first chemical functional groups site-specifically transferred to Fc lysines 246 and/or 248.
Kits and methods for preparing SSAI constructs and antibody conjugates.
Dosing/regimen considerations for antibody therapeutics, including dose ranges in mg/kg, administration schedules, and administration routes for modified antibody/biological agent treatments.
Use of site-specific click chemistry functional group linkers and multicomponent SSFI/peptide constructs for producing modified antibody constructs with click chemistry functionality.
Preparation of a VC linker (DD2) culminating in an SN38 conjugate, as described in the partial content.
Cancer treatment, including breast cancer, using antibody-drug conjugate (ADC) architecture with complementary click groups, as described in the pharmaceutical compositions and pharmaceutical methods.
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