Tri-specific binding molecules that specifically bind to multiple cancer antigens
Inventors
Bonvini, Ezio • Moore, Paul A. • Li, Jonathan C. • Johnson, Leslie S. • Shah, Kalpana
Assignees
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Publication Number
US-11697684-B2
Publication Date
2023-07-11
Expiration Date
Abstract
The present invention relates to Tri-Specific Binding Molecules, which are multi-chain polypeptide molecules that possess three Binding Domains and are thus capable of mediating coordinated binding to three epitopes. The Tri-Specific Binding Molecule is preferably characterized in possessing binding domains that permit it to immunospecifically bind to: (1) an epitope of a first Cancer Antigen, (2) an epitope of a second Cancer Antigen, and (3) an epitope of a molecule that is expressed on the surface of an immune system effector cell, and are thus capable of localizing an immune system effector cell to a cell that expresses a Cancer Antigen, so as to thereby facilitate the killing of such cancer cell.
Core Innovation
The invention provides a multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes by covalently complexed polypeptide chains and includes an Fc Domain. It defines Antigen-Binding Domain I, Antigen-Binding Domain II, and Antigen-Binding Domain III for an epitope of an Effector Cell Antigen, a first Cancer Antigen, and a second Cancer Antigen. The tri-specific binding architecture includes EphA2/CD3/gpA33 and gpA33×CD3×DR5 embodiments.
A defined domain architecture is provided for first, second, and third polypeptide chains in N-terminus to C-terminus direction, including VL and VH domains, linkers, heterodimer-promoting domains, CH2-CH3 domains, and Ig-related domains such as CH1, CL, and cysteine-containing domains. The Fc Domain is formed by association of CH2-CH3 domains of the first and third polypeptide chains. E-coil and K-coil heterodimer-promoting domains, knob-into-hole heterodimerization pairs, and sequence-defined linker and domain boundary mappings are described.
The document further discloses specified sequence components by SEQ ID NO, corresponding polynucleotides, and CDR-defined antigen-binding specificity for selected light-chain variable and heavy-chain variable domains. Functional examples described include coordinated or simultaneous dual cancer antigen binding with synergistic target binding and cytotoxicity mediated by trispecific molecules. Anti-DR5 examples are also described with TRAIL-binding non-blocking behavior, species specificity, epitope differentiation, and unexpected cytotoxic superiority.
Claims Coverage
The claim set covers a multi-chain tri-specific binding molecule with three epitopes and an Fc Domain formed by CH2-CH3 association. The inventive features focus on the three-chain architecture, epitope assignment to an effector-cell antigen and two cancer antigens, sequence-defined linkers and heterodimer-promoting domains, CDR/SEQ ID-based specificity, and CH2-CH3 substitutions that alter FcγR-mediated effector function.
Multi-chain tri-specific binding molecule with effector cell and two cancer antigens
A multi-chain polypeptide-containing Tri-Specific Binding Molecule that immunospecifically binds to three different epitopes, comprising three different polypeptide chains covalently complexed together, Antigen-Binding Domains I, II, and III, and a Fc Domain; one epitope is an Effector Cell Antigen epitope and the other two are cancer antigen epitopes.
Defined three-chain domain architecture with Fc formed by CH2-CH3 association
First, second, and third polypeptide chains comprise specified VL/VH domains, linkers, heterodimer-promoting domains, cysteine-containing domains, CH1, CL, and CH2-CH3 domains, with the CH2-CH3 domains of the first and third chains associating to form the Fc Domain.
Linker and heterodimer-promoting domain sequence selections
Linker 1, Linker 2, Linker 3, and Linker 4 comprise specified SEQ ID NOs; the heterodimer-promoting domains are E-coil and K-coil domains with specified SEQ ID constraints; knob-into-hole Fc variants are also described.
Effector and cancer antigen epitope assignment
One of Epitope I, Epitope II, or Epitope III is an epitope of an Effector Cell Antigen, a second is an epitope of a first Cancer Antigen, and a third is an epitope of a second Cancer Antigen.
CDR-defined antigen binding specificity
One of Epitope I, Epitope II, or Epitope III is an epitope of a cancer antigen, and the antigen-binding domain immunospecifically binds the epitope via specified CDRs and corresponding light-chain variable and heavy-chain variable domains from SEQ ID NOs.
CH2-CH3 substitutions altering FcγR-mediated effector function
Substitutions are introduced in the CH2-CH3 domain of the first and third polypeptide chains relative to SEQ ID NO:1, resulting in an Fc domain with altered FcγR-mediated effector function.
Overall, the claims define a covalently complexed tri-specific binding molecule with a composite Fc Domain, explicit VL/VH-based antigen-binding domain formation, heterodimer-promoting E-coil/K-coil architecture, specified linker sequences, and constraints for effector-cell and cancer-antigen targeting. Additional refinements constrain binding specificity using CDR/SEQ ID-defined variable domains and permit CH2-CH3 substitutions to alter FcγR-mediated effector function.
Stated Advantages
Co-localization of effector cells with cancer cells to facilitate killing.
Altered FcγR-mediated effector function through CH2-CH3 domain substitutions.
Synergistic target binding described for coordinated or simultaneous dual cancer antigen binding.
Unexpected cytotoxic superiority of DR5 mAb1/2 is described in the document.
TRAIL-binding non-blocking behavior is described for anti-DR5 antibody examples.
Documented Applications
Effector cell binding together with binding to a first Cancer Antigen and a second Cancer Antigen.
Cancer targeting through co-localization of effector cells with cancer cells.
Immunospecific tri-specific binding and cytotoxicity mediated by trispecific molecules, including examples involving anti-DR5 antibodies with epitope differentiation and TRAIL-binding non-blocking behavior.
Coordinated or simultaneous dual cancer antigen binding with synergistic target binding in cancer contexts.
Pharmaceutical composition, dosing/formulation/use sections are referenced in the provided content.
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