B7H4-targeted antibody-drug conjugates and methods of use thereof
Inventors
Lowinger, Timothy B. • Chin, Chen-Ni • DAMELIN, Marc I. • Toader, Dorin
Assignees
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Publication Number
US-11964024-B2
Publication Date
2024-04-23
Expiration Date
Abstract
The present disclosure relates generally to antibody-drug conjugates comprising monoclonal antibodies that specifically bind the human B7-H4 in soluble form, or membrane bound (i.e., when expressed on a cell surface) and to methods of using these conjugates as therapeutics and/or diagnostics.
Core Innovation
The disclosure defines isolated antibodies that specifically bind B7-H4 and are characterized by variable heavy chain complementarity determining regions CDRH1 GFIVSRNY, CDRH2 IYGSGRT, and CDRH3 ARDADYGLDV or ARDADYGMDV, together with variable light chain complementarity determining regions CDRL1 QSVSSSY, CDRL2 GAS, and CDRL3 QQYGSSPLYT. The invention extends these antibodies into B7-H4 antibody-drug conjugates of Formula (XXXVII) with covalently linked linker-drug moieties and defined structural embodiments.
The Formula (XXXVII) conjugates include drug attachment to a heavy chain via a linker moiety at an asparagine residue at position 296 or 297, depending on the stated numbering reference, and are repeatedly described with d13 about 2. The conjugates are additionally characterized by carbohydrate components GlcNAc, Fuc, and GalNAc, and by embodiments specifying heavy and light chain sequence sets or heavy and light variable and constant region sequences.
The disclosure also describes multifunctional linker architectures, including a releasable assembly unit, a peptide moiety, and a hydrophilic group connected to the drug units. Additional structural embodiments include glycoengineering-related features, site-specific conjugation at N297 using an azido-functionalized position and azide-alkyne click chemistry to form a triazole linkage, and endoglycosidase-mediated remodeling to generate terminal GlcNAc and glycosyltransferase-mediated conversion to modified GlcNAc.
Claims Coverage
The consolidated claim coverage centers on a B7-H4-binding isolated antibody defined by specific heavy- and light-chain CDR sequences and on multiple B7-H4 antibody-drug conjugate embodiments of Formula (XXXVII). Across the independent claim families, the recurring inventive features are the antibody CDR definition, drug attachment to the heavy chain at a specified asparagine residue, d13 about 2, and inclusion of GlcNAc, Fuc, and GalNAc, with additional variants specifying heavy and light chain sequence sets or variable and constant region sequences.
B7-H4 binding isolated antibody defined by CDR sequences
An isolated antibody that specifically binds B7-H4 comprising CDRH1 GFIVSRNY, CDRH2 IYGSGRT, CDRH3 ARDADYGLDV or ARDADYGMDV, CDRL1 QSVSSSY, CDRL2 GAS, and CDRL3 QQYGSSPLYT.
B7-H4 antibody-drug conjugate of Formula (XXXVII) with heavy-chain asparagine attachment
A B7-H4 antibody-drug conjugate of Formula (XXXVII) wherein ANTIBODY binds B7-H4, the drug is attached to a heavy chain of the antibody via a linker moiety at an asparagine residue at position 296 or 297 according to the stated numbering reference, d13 is about 2, and the conjugate includes GlcNAc, Fuc, and GalNAc.
B7-H4 antibody-drug conjugate of Formula (XXXVII) with heavy and light chain sequences
A B7-H4 antibody-drug conjugate of Formula (XXXVII) wherein ANTIBODY binds B7-H4 and comprises a heavy chain sequence set forth in SEQ ID NO: 45 and a light chain sequence set forth in SEQ ID NO: 52, with drug attachment to the heavy chain at asparagine 296 according to SEQ ID NO: 45, d13 about 2, and GlcNAc, Fuc, and GalNAc.
B7-H4 antibody-drug conjugate of Formula (XXXVII) with heavy and light variable sequences
A B7-H4 antibody-drug conjugate of Formula (XXXVII) wherein ANTIBODY binds B7-H4 and comprises a heavy chain variable sequence of SEQ ID NO: 44 and a light chain variable sequence of SEQ ID NO: 50, with drug attachment to the heavy chain at asparagine 296 according to SEQ ID NO: 45, d13 about 2, and GlcNAc, Fuc, and GalNAc.
B7-H4 antibody-drug conjugate of Formula (XXXVII) with heavy and light variable and constant regions
A B7-H4 antibody-drug conjugate of Formula (XXXVII) wherein ANTIBODY binds B7-H4 and comprises a heavy chain variable sequence of SEQ ID NO: 44, a heavy chain constant region of SEQ ID NO: 6, a light chain variable sequence of SEQ ID NO: 50, and a light chain constant region of SEQ ID NO: 51, with drug attachment to the heavy chain at asparagine 296 according to SEQ ID NO: 45, d13 about 2, and GlcNAc, Fuc, and GalNAc.
B7-H4 antibody-drug conjugate with releasable multifunctional linker architecture
A B7-H4 antibody-drug conjugate comprising one or more covalently linked linker-drug moieties in which a multifunctional linker uses a releasable assembly unit and includes a peptide moiety between the antibody and a hydrophilic group connected to the drug units.
Collectively, the claims define a B7-H4-specific isolated antibody by specified CDR amino acid sequences and define multiple B7-H4 antibody-drug conjugates of Formula (XXXVII) that share structural constraints including heavy-chain drug attachment at a specified asparagine residue, d13 about 2, and inclusion of GlcNAc, Fuc, and GalNAc. Additional variants further specify the antibody by heavy/light chain sequence sets or variable and constant region sequences, together with a broader multifunctional linker architecture.
Stated Advantages
Increased stability and reduced degradation via inert triazole/oxime-like moieties.
Documented Applications
Treatment of B7-H4 positive cancer selected from bile duct carcinoma, breast cancer, endometrial cancer, ovarian cancer, non-small cell lung cancer, small cell lung cancer, uterine cancer, thyroid cancer, kidney cancer, head and neck cancer, gastric cancer, melanoma, cholangial carcinoma, pancreatic cancer, colon cancer, and bladder cancer.
B7-H4 STING agonist antibody-drug conjugates are functionally tested for cellular STING activation.
Functional evaluation includes ELISA/FACS binding, polyreactivity scoring, affinity by BLI (Kd), and cellular STING activation.
References are made to in vivo efficacy and PK for the resulting ADCs/conjugates in mouse xenograft models (MX-1 TNBC, HBCx PDX).
Therapeutic use is described for B7-H4-positive cancers, including methods of treating or preventing disease or cancer.
Combination therapy strategies are described including combination with PD-1/PD-L1 inhibitors and other agents for cancer treatment.
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