Anti-ROR1 antibody conjugates, compositions comprising anti ROR1 antibody conjugates, and methods of making and using anti-ROR1 antibody conjugates
Inventors
Gakhal, Amandeep • YU, Abigail • Stafford, Ryan • Hanson, Jeffrey • Yam, Alice • Bajjuri, Krishna • Maderna, Andreas • Abrahams, Cristina • Li, Xiaofan • Yin, Gang • Wen, Miao • Bedard, Kristin • Calarese, Daniel • Kiefel, Helena
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12144869-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present disclosure relates to antibodies and antibody conjugates, for instance antibody drug conjugates, with binding specificity for receptor tyrosine kinase orphan receptor 1 (ROR1) and its isoforms and homologs, and compositions comprising the antibodies or antibody conjugates, including pharmaceutical compositions. Also provided are methods of producing the antibodies and antibody conjugates and compositions thereof as well as methods of using the antibodies and antibody conjugates and compositions thereof, such as in therapeutic and diagnostic methods.
Core Innovation
The invention relates to a conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1). The antibody is linked site-specifically to at least one payload moiety and comprises one or more non-natural amino acids. The antibody is defined by particular V_H and V_L regions, including specified CDR-H1, CDR-H2, CDR-H3 and CDR-L1, CDR-L2, CDR-L3 sequence identifiers, with alternative configurations provided by sets (a), (b), and (c).
The conjugate architecture further specifies non-natural amino acids including para-azidomethylphenylalanine and p-azido-methyl-L-phenylalanine, with attachment at defined heavy-chain and light-chain sites such as HC180, HC241, HC404, and LC42. The disclosed embodiments also refer to a defined n2 value or range, and to each linker-payload being bonded to one para-azidomethylphenylalanine residue side chain. Other described linker concepts include L2, L3, and L4 motifs, together with hydrophilic spacer, polymer, peptide, and saccharide or hexose-related components.
The disclosure further describes antibody conjugate frameworks using COMP-LINK-PAY, SG-W4-RT, and related linker moieties, including release trigger groups and eliminator/releasing reactions. It also describes payload moieties and linker-payload constructs such as DBCO-PEG-linked Exatecan, Hemiasterlin, and other payload categories, as well as linker-payload families with validated chemical structures and characterization identifiers. The overall disclosure centers on a site-specifically linked anti-ROR1 antibody conjugate architecture built from defined CDR sequence sets and non-natural amino acid-based payload attachment.
Claims Coverage
The claim coverage centers on a ROR1-binding antibody conjugate with site-specific payload linkage and one or more non-natural amino acids, with the antibody defined by three alternative V_H/V_L CDR sequence sets. Dependent coverage further narrows the non-natural amino acid identity and position, defines para-azidomethylphenylalanine attachment sites and n2 constraints, and includes treatment of ROR1-expressing specified cancer types.
Site-specific ROR1-binding antibody conjugate with non-natural amino acids
A conjugate comprising an antibody that specifically binds to receptor tyrosine kinase orphan receptor 1 (ROR1), the antibody being linked site-specifically to at least one payload moiety and comprising one or more non-natural amino acids.
Defined heavy- and light-chain CDR sequence sets
The antibody comprises alternative configurations (a), (b), or (c) defined by V_H CDR-H1, CDR-H2, and CDR-H3 SEQ ID NOs and V_L CDR-L1, CDR-L2, and CDR-L3 SEQ ID NOs.
Non-natural amino acid selection by numbering schemes
The one or more non-natural amino acids are selected from a specified list using the Kabat, Chothia, or EU numbering scheme.
Para-azidomethylphenylalanine incorporation
The one or more non-natural amino acids are p-azidomethylphenylalanine or p-azido-methyl-L-phenylalanine.
Defined attachment sites and n2 constraint
Para-azidomethylphenylalanine residues are attached at HC180, HC241, HC404, and LC42 sites, with n2 equal to 8 in one embodiment and an integer from 1 to 10 in another.
Treatment of ROR-1-expressing cancers by administering the conjugate
A method for treating a disease or condition in a subject by administering an effective amount of the conjugate, where the disease is a ROR-1-expressing specified cancer type.
Overall, the claims are directed to a ROR1-targeting antibody conjugate defined by specific V_H and V_L CDR sequence identifiers and site-specific linkage to payload moieties through non-natural amino acids. Dependent features further specify para-azidomethylphenylalanine variants, attachment positions, n2 limitations, and therapeutic administration for ROR1-expressing cancers.
Stated Advantages
Improved Fc thermal stability after conjugation.
Antigen-dependent cytotoxicity against ROR1-positive cells demonstrated by competition with unconjugated antibody.
In vivo preservation of linker-payload integrity in mice.
Efficacy comparisons of conjugates/payloads in xenograft and PDX tumor models.
Synergy with a PARP inhibitor and immunogenicity/toxicology-forward characterization including immunogenic cell death markers and monocyte activation readouts.
Documented Applications
In vitro cytotoxicity against ROR1-positive and ROR1-negative cells.
In vivo efficacy in xenograft tumor models and PDX tumor models.
Combination with PARP inhibitor olaparib.
Treating a disease or condition in a subject by administering an effective amount of the conjugate of claim 1, where the disease is a ROR-1-expressing specified cancer type.
Reducing ROR1-expressing cell proliferation.
Interested in licensing this patent?