Immunoconjugates and methods
Inventors
Han, Xiaojun • ORR, SUVI TUULA MARJUKKA • Bunker, Kevin Duane • HUANG, Peter Qinhua • Fischer, Kimberlee
Assignees
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Publication Number
US-12285492-B2
Publication Date
2025-04-29
Expiration Date
Abstract
Immunoconjugates of the Formula (I) include a linking group for linking an antibody targeting ligand (Ab) to a drug (D). Embodiments of such immunoconjugates are useful for delivering the drug to selected cells or tissues, e.g., for the treatment of cancer. Ab-[S-L1-L2-L3-L4-L5-L6-L7-D]n (I)
Core Innovation
The disclosure describes an immunoconjugate having Formula (I), in which Ab is an antibody or an antigen-binding fragment thereof, connected through a chain segment including linker positions L1 to L7 and a drug moiety D. The linker architecture includes defined presence and absence relationships, including L2 being absent or defined by Z1 and Z2, L6 being absent, and L7 being absent, with L3 as -(CH2)n1-C(=O) and L4 as a tetrapeptide residue represented by SEQ ID NO: 43 (GGFG).
L5 is defined as -[NH(CH2)n2]n3-, where n2 is an integer from 0 to 6 and n3 is an integer from 0 to 2, and the conjugation architecture is constrained by both peptide and spacer structural definitions within Formula (I). The drug moiety D is defined by Formula (II), with R1 and R2 individually selected from hydrogen, fluoro, methoxy, methyl, difluoromethyl, and -O-(CH2)-O- such that R1 and R2 taken together form a ring, together with the specified constraints for R3, R4, X1, X2, n4, n5, R7, R9, and n.
The disclosed Ab is directed to a cancer cell surface by binding to a selected receptor, including human receptor tyrosine kinase like orphan receptor 1 (ROR1) and/or HER2 as described in the provided portion. The immunoconjugate embodiments include variable linker substituent options for Z1/Z2 and incorporate the specified linker and drug moiety structures, and the document also describes immunoconjugate embodiments in which D is a cytotoxic anti-cancer drug moiety, including exatecan.
Claims Coverage
The independent claim coverage centers on a Formula (I) immunoconjugate with a specified antibody-linker-drug architecture and a drug moiety defined by Formula (II). Across the consolidated claim set, the main inventive features are the constrained linker composition with SEQ ID NO: 43 (GGFG), the specified ring-forming drug scaffold constraints, and antibody specificity refinements toward ROR1 and antibody sequence identity features.
Immunoconjugate architecture with Ab, linker positions, and drug moiety D
An immunoconjugate having Formula (I) wherein Ab is an antibody or an antigen-binding fragment thereof, connected through [S-L1-L2-L3-L4-L5-L6-L7] with specified presence or absence of L2, L6, and L7, and a drug moiety D.
Specified linker composition at L3, L4, and L5 with Z1 and Z2 options
L3 is -(CH2)n1-C(=O), where n1 is an integer of 1 to 6; L4 is a tetrapeptide residue represented by SEQ ID NO: 43 (GGFG); L5 is -[NH(CH2)n2]n3- where n2 is an integer from 0 to 6 and n3 is an integer from 0 to 2; and L2 is absent or Z1 and Z2 are each hydrogen.
Drug scaffold Formula (II) constraints for ring-closed R1/R2 and fixed integer values
D is a drug moiety having Formula (II) wherein R1 and R2 are each individually selected from hydrogen, fluoro, methoxy, methyl, difluoromethyl, and -O-(CH2)-O- such that R1 and R2 taken together form a ring; R3 is hydrogen; R4 is unsubstituted -(C1-C6 alkyl)-X2; X1 is -O-; X2 is -OR9; n4 is 2; n5 is 0; R7 is H; R9 is L5; and n is an integer from 1 to 10.
Antibody binding to ROR1
An immunoconjugate in which the antibody Ab specifically binds the human receptor tyrosine kinase like orphan receptor 1 (ROR1).
Antibody CDRs with specified sequence identities via SEQ ID NOs
An immunoconjugate whose antibody Ab includes specific variable heavy-chain and variable light-chain regions containing CDR sequences identified by SEQ ID NOs, including VH CDR1 (SEQ ID NO: 1), VH CDR2 (SEQ ID NO: 2), VH CDR3 (SEQ ID NO: 3), VL CDR1 (SEQ ID NO: 8), VL CDR2 (AAS), and VL CDR3 (SEQ ID NO: 10).
Overall claim coverage is concentrated on a Formula (I) immunoconjugate with a particular linker residue at L4 (SEQ ID NO: 43 (GGFG)), defined linker elements at L3 and L5, absent L6 and L7, and a constrained drug scaffold (Formula (II)) with ring-closed R1/R2 and fixed n4 and n5 values. The antibody specificity is further refined toward ROR1 and by defining CDR sequences and sequence-identity requirements.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a cancer or tumor by administering an effective amount of the immunoconjugate (as defined in claim 1) to a subject having the cancer or the tumor.
Treating a cancer or tumor selected from a specified list of cancer types, including lung cancer, urothelial cancer, colorectal cancer, prostate cancer, ovarian cancer, pancreatic cancer, breast cancer, bladder cancer, gastric cancer, gastrointestinal stromal tumor, uterine cervix cancer, esophageal cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular cancer, colon cancer, rectal cancer, endometrial cancer, uterine cancer, salivary gland cancer, kidney cancer, vulval cancer, thyroid cancer, penis cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, and sarcoma.
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