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-12280121-B2
Publication Date
2025-04-22
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 represented by a structure in which Ab is an antibody or an antigen-binding fragment thereof, and n is an integer from 1 to 10. The immunoconjugate includes a multi-part linker with parts L1 to L7 and D attached, linking the Ab to a drug payload. The document provides structural definitions for the linker components, substituents, and drug moieties, including embodiments and variants expressed through formulas.
A central aspect of the immunoconjugate is the selection and definition of the drug moiety D, including a cytotoxic anti-cancer drug moiety and a drug of Formula (II) with further substituent definitions. The document also introduces alternative drug compound definitions using Formula (IV) and sub-formulas IVa to IVc, with broad variable definitions, and specifies that Formula (IV) does not represent deruxtecan or exatecan. The linker architecture and drug moiety definitions are integrated to support the overall immunoconjugate structure.
The immunoconjugate includes an antibody or antigen-binding fragment that specifically binds human receptor tyrosine kinase-like orphan receptor 1 (ROR1) or binds ROR1/cancer cells. Representative immunoconjugate structures are presented with Z1 and Z2 substitutions, together with pharmaceutical composition, medicament, uses and methods of treatment, and synthesis/exemplified compounds.
Claims Coverage
The claim coverage centers on an immunoconjugate defined by antibody or antigen-binding fragment, ROR1-specific binding, specified VH/VL CDR sequences and sequence-identity limitations, with cancer or tumor treatment and composition uses, together with a conjugate defined by a represented structure or salt and modular linker variants to a cytotoxic anti-cancer drug moiety. The consolidated material includes four inventive features for the immunoconjugate claims and one structural feature for the conjugate claims.
Immunoconjugate structure with antibody and n range
An immunoconjugate represented by a structure in which Ab is an antibody or an antigen-binding fragment thereof, and n is an integer from 1 to 10.
Antibody specifically binding ROR1
The immunoconjugate in which the antibody (Ab) specifically binds human receptor tyrosine kinase-like orphan receptor 1 (ROR1).
Antibody variable regions with specified CDR sequences
An immunoconjugate in which the antibody (Ab) comprises specified variable heavy and variable light chain regions with particular CDR amino-acid sequences identified by SEQ ID NOs, including VHCDR1 (SEQ ID NO: 1), VHCDR2 (SEQ ID NO: 2), VHCDR3 (SEQ ID NO: 3), VLCDR1 (SEQ ID NO: 8), VLCDR2 (AAS), and VLCDR3 (SEQ ID NO: 10).
VH and VL at least 80% identity while preserving CDRs
An immunoconjugate in which the antibody (Ab) comprises specific variable heavy chain and variable light chain regions with at least 80% sequence identity to given SEQ ID NO amino acid sequences while preserving specified CDR sequences.
Modular linker architecture with variable presence of linker segments
The conjugate includes modular linker segments L2 through L7 that connect Mi to D, with embodiments in which one or more segments may be absent, including cases where L2 is absent and cases where L2, L6, and L7 are absent in different combinations.
Overall, the claim set covers an immunoconjugate defined by a structure with an antibody or antigen-binding fragment and an n range, narrowed by a ROR1-binding antibody and further defined by specified VH/VL CDR sequences and sequence-identity constraints, with a conjugate defined by a represented structure or salt and modular linker variants to a cytotoxic anti-cancer drug moiety.
Stated Advantages
Improved internalization kinetics for selected antibodies compared to UC961, as stated in the described internalization results.
Weaker binding (ATX-P-885) may improve tumor penetration, as asserted in the provided description.
Documented Applications
Cancer or tumor treatment by administering an effective amount of the immunoconjugate to a subject with the cancer or the tumor.
Pharmaceutical compositions comprising the immunoconjugate with a pharmaceutically acceptable excipient.
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