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-11806405-B1
Publication Date
2023-11-07
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 document relates to immunoconjugates having Formula (I) in which an antibody or an antigen-binding fragment thereof specifically binds the extracellular domain of human receptor tyrosine kinase like orphan receptor 1 (ROR1) and is linked to a drug moiety through a defined linker sequence including L1, L2, L3, L4, L5, L6, and L7, with n defined as an integer from 1 to 10. The linker architecture includes a tetrapeptide residue as L4, with optional or absent linker segments as defined.
The drug moiety D corresponds to a compound of Formula (II) with constrained substituent selections and ring-forming options for R1 and R2, together with defined parameters for R3, R4, X1, X2, R5, R6, m, n4, and n5. The document also includes a proviso that Formula (II) does not represent exatecan, and discloses conjugates of Formula (III) that link the same constrained Formula (II) drug moiety through the specified linker scaffold.
The document further describes anti-ROR1 monoclonal antibodies, including ATX-P-875, ATX-P-885, and ATX-P-890, characterized by cell-based binding saturation, receptor internalization assays, epitope binning, SPR, and AC-SINS developability assessment. It also includes ADC-related content with in vitro evaluation and CTG assay potency results for ROR1 ADCs with multiple linker/payloads, together with anti-ROR1 antibody development and characterization assays.
Claims Coverage
The consolidated claims coverage includes four independent claims. Across them, the inventive features center on a Formula (I) immunoconjugate with a ROR1-specific antibody or antigen-binding fragment and a defined linker-to-drug architecture, a constrained Formula (II) drug-moiety scaffold with an express exclusion of exatecan, a constrained Formula (IVa) compound, and a Formula (III) conjugate that links the same Formula (II) drug moiety.
Immunoconjugate with ROR1-binding antibody and defined linker architecture
An immunoconjugate having Formula (I), where Ab is an antibody or an antigen-binding fragment thereof that specifically binds the extracellular domain of human receptor tyrosine kinase like orphan receptor 1 (ROR1), and the linker sequence includes defined L1 to L7 presence/absence and substituent options, with L4 as a tetrapeptide residue and n an integer from 1 to 10.
Constrained Formula (II) compound excluding exatecan
A compound of Formula (II), or a pharmaceutically acceptable salt thereof, with constrained selections for R1, R2, R3, R4, X1, X2, R5, R6, m, n4, and n5, and with the proviso that Formula (II) does not represent exatecan.
Formula (IVa) compound with constrained ring-forming substituents
A compound, or a pharmaceutically acceptable salt thereof, represented by Formula (IVa), with constrained selections for R1, R2, R3, R4, X1, X2, R5, R6, R7, and m.
Formula (III) conjugate with Formula (II) drug moiety
A conjugate having Formula (III) with the specified linker scaffold, L2 absent, L3 and L4 defined, optional L5, and D as a drug moiety that is a compound of Formula (II) with the specified structure constraints.
The claims collectively define a ROR1-specific Formula (I) immunoconjugate with a detailed linker architecture and drug moiety attachment, together with related Formula (II), Formula (IVa), and Formula (III) chemical embodiments anchored by the same constrained scaffold language.
Stated Advantages
Not explicitly described in patent.
Documented Applications
In vitro ADC evaluation assays are disclosed, including CTG cell viability/IC50 on ROR1+ lines, human hepatocyte intrinsic clearance, human liver microsome clearance, and PAMPA permeability.
Anti-ROR1 antibody development and characterization assays are disclosed, including cell binding saturation, internalization, epitope binning, SPR binning, AC-SINS developability, and ADC potency tables.
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