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-12186403-B2
Publication Date
2025-01-07
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 invention relates to an immunoconjugate of Formula (I) in which an antibody or an antigen-binding fragment is linked through a multi-linker comprising L1 to L7 to a drug moiety D. The linker/residue components are defined with specific optionality, including L2 being absent, L4 being a tetrapeptide residue, and selected presence or absence relationships among L5, L6, and L7, with integer ranges for n1, n2, n3, and n.
The immunoconjugate is defined so that the antibody or antigen-binding fragment specifically binds the extracellular domain of human receptor tyrosine kinase like orphan receptor 1 (ROR1). The binding antibody is characterized by a heavy chain comprising VHCDR1, VHCDR2, and VHCDR3 with amino acid sequences identified as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and a light chain comprising VLCDR1, VLCDR2, and VLCDR3 with amino acid sequences identified as SEQ ID NO:8, AAS, and SEQ ID NO:10.
The document further describes embodiments in which D is a cytotoxic anti-cancer drug moiety, including exatecan in described embodiments, together with defined substituent options for Z1 and Z2 and example tetrapeptide linker residue selections including GGFG, EGGF, SGGF, and KGGF. It also describes development and characterization of novel anti-ROR1 monoclonal antibodies and therapeutic and formulation embodiments including pharmaceutical compositions and administering an effective amount of the immunoconjugate to a cancer or tumor subject.
Claims Coverage
The independent claims center on an immunoconjugate architecture with a defined linker structure and drug moiety, and an antibody or antigen-binding fragment that specifically binds the extracellular domain of human ROR1 using defined CDR sequences. Three independent claims are present across the input items.
Immunoconjugate of Formula (I) with defined multi-linker and drug moiety D
An immunoconjugate having Formula (I), wherein Ab is an antibody or antigen-binding fragment; L2 is absent; Z1 and Z2 are each individually hydrogen, halogen, NO2, —O—(C1-C6 alkyl), or C1-C6 alkyl; L4 is a tetrapeptide residue; L5 is absent or —[NH(CH2)n2]n3—; L6 is absent or L7 is absent; D is a drug moiety; and n is an integer from 1 to 10, wherein the antibody or antigen-binding fragment specifically binds the extracellular domain of human ROR1.
ROR1-binding immunoconjugate with specified antibody CDR sequences
An immunoconjugate selected from the group consisting of the enumerated embodiments, wherein Ab is an antibody or antigen-binding fragment comprising a heavy chain with VHCDR1 comprising SEQ ID NO:1, VHCDR2 comprising SEQ ID NO:2, and VHCDR3 comprising SEQ ID NO:3, and a light chain with VLCDR1 comprising SEQ ID NO:8, VLCDR2 comprising AAS, and VLCDR3 comprising SEQ ID NO:10, wherein the antibody or antigen-binding fragment specifically binds the extracellular domain of human ROR1.
ROR1-binding immunoconjugate with specified heavy and light variable region sequences
An immunoconjugate selected from the group consisting of the enumerated embodiments, wherein Ab is an antibody or antigen-binding fragment comprising a heavy chain comprising VHCDR1 comprising SEQ ID NO:1, VHCDR2 comprising SEQ ID NO:2, and VHCDR3 comprising SEQ ID NO:3, and a light chain comprising VLCDR1 comprising SEQ ID NO:8, VLCDR2 comprising AAS, and VLCDR3 comprising SEQ ID NO:10, wherein the antibody or antigen-binding fragment specifically binds the extracellular domain of human ROR1.
The claims coverage centers on immunoconjugates whose antibody component specifically binds the extracellular domain of human ROR1 and whose conjugate architecture is defined by Formula (I) linker and drug moiety parameters, with selected embodiments tied to specified antibody CDR sequences and enumerated immunoconjugate structures.
Stated Advantages
The immunoconjugate is associated with evaluation of ADC payload performance through assay outputs and ROR1-antibody payload potency benchmarking context.
Documented Applications
Pharmaceutical compositions.
Administering an effective amount of the immunoconjugate to a cancer or tumor subject.
ADC evaluation.
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