Antibody-drug conjugate comprising modified antibody
Inventors
Park, Soon Jae • Chung, Hye-Shin • Lee, Sunbae • Byun, Minsoo
Assignees
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Publication Number
US-12090210-B2
Publication Date
2024-09-17
Expiration Date
Abstract
The present disclosure relates to an antibody-drug conjugate in which a modified antibody comprising a motif having a specific structure at the end of the antibody is conjugated to a drug via a linker, and a composition comprising the same, and more particularly to a modified antibody-drug conjugate (mADC) comprising a modified antibody that has a significantly increased conjugation yield of drug due to a motif bound to the heavy chain or light chain C-terminus of the antibody, and to a composition comprising the same.
Core Innovation
The invention relates to modified antibody-drug conjugates (mADCs) in which a modified antibody comprising a motif at an end of the antibody is bound to a drug by a linker. The motif is represented by a structural formula having two motif segments Mmotif1 and Mmotif2, selected from ACGHA (SEQ ID NO:1) or AHGCA (SEQ ID NO:2), and AXGHA (SEQ ID NO:3) or AHGXA (SEQ ID NO:4), with specified constraints on the X position as an amino acid other than cysteine, and by peptide residues Xa and Xb that independently consist of 0 to 20 amino acid residues selected from A, S, and G, and by integers n1 and n2 ranging from 1 to 10.
In the disclosed conjugates, the motif is attached at either the heavy-chain C-terminus or the light-chain C-terminus of the antibody, and the resulting antibody motif architecture is used to enable site-specific drug conjugation. The disclosed linker chemistry includes linker components with reactive functional groups for cysteine/motif thiol coupling, together with a self-cleaving spacer.
The motif/linker design is presented as improving the site-specific drug conjugation yield compared with first-generation and other site-specific conjugation approaches. Specific motif variants, including FM2b/HM2b variants, yield substantially higher conjugation yields than related motif arrangements while maintaining comparable in vitro cell growth inhibition after purification to equal DAR.
The disclosed mADCs are reported to show acceptable storage stability and aggregate behavior, and example payloads and antibody targets include MMAE and named targets such as folate receptor and HER2.
Claims Coverage
Independent claim 1 defines the mADC architecture with a defined C-terminal motif at an end of the antibody bound to a drug by a linker. Across the dependent claims provided, additional inventive features refine the motif location, linker architecture, conjugation attachment site, allowed drug/toxin payload set, and specific antibody formats (IgG2/IgG4 regions and Fab-Fc).
Defined C-terminal motif bound via linker in an antibody-drug conjugate
An antibody-drug conjugate in which a modified antibody comprising a motif at an end of the antibody is bound to a drug by a linker, where Mmotif1 is ACGHA (SEQ ID NO:1) or AHGCA (SEQ ID NO:2), Mmotif2 is AXGHA (SEQ ID NO:3) or AHGXA (SEQ ID NO:4) with specified residue restrictions on X, Xa and Xb are each a peptide consisting of 0 to 20 amino acid residues selected from A, S, and G, and n1 and n2 are integers from 1 to 10.
Motif introduced at heavy-chain C-terminus
An antibody-drug conjugate in which a motif is introduced at the heavy-chain C-terminus of the antibody.
Linker includes reactive functional group and self-cleaving spacer
An antibody-drug conjugate where the linker includes a reactive functional group, binds to a specified motif and an amino acid, and includes a self-cleaving spacer.
Drug conjugated to cysteine residue (or X) within motif
The antibody-drug conjugate in which the drug is conjugated to a cysteine residue or X within the motif.
Conjugated drug selected from specified cytotoxic/toxin agents
The antibody-drug conjugate in which the conjugated drug is selected from a specified group of cytotoxic drug/toxin agents.
Antibody defined as IgG2/IgG4 regions or IgG2/IgG4 Fab-Fc
An antibody-drug conjugate where the antibody component is defined as either IgG2/IgG4 variable regions with CH1, CH2 and CH3, or an IgG2/IgG4 Fab and an IgG2/IgG4 Fc.
Overall, the claims coverage is centered on an antibody-drug conjugate architecture defined by a specific motif structure at an antibody end, with dependent refinements constraining motif placement (heavy-chain C-terminus), linker features (reactive functional group and self-cleaving spacer), conjugation attachment (to cysteine or X in the motif), the allowed cytotoxic payload set, and specific IgG2/IgG4 antibody format definitions.
Stated Advantages
Improved site-specific drug conjugation yield compared with first-generation and other site-specific conjugation methods.
Substantially higher conjugation yields for specific motif variants, including FM2b/HM2b, than related motif arrangements.
Comparable in vitro cell growth inhibition after purification to equal DAR.
Acceptable storage stability and aggregate behavior.
Documented Applications
Cancer treatment context using an antigen-specific anticancer payload, with examples including mADCs using MMAE and antibody targets such as folate receptor and HER2.
Use with KB cells overexpressing the folate receptor, including reporting of in vitro cell growth inhibition after purification to equal DAR.
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