LAG-3-binding molecules and methods of use thereof
Inventors
La Motte-Mohs, Ross • Shah, Kalpana • Smith, Douglas H. • Johnson, Leslie S. • Moore, Paul A. • Bonvini, Ezio • Koenig, Scott
Assignees
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Publication Number
US-11858991-B2
Publication Date
2024-01-02
Expiration Date
Abstract
The present invention is directed to the anti-LAG-3 antibodies: LAG-3 mAb 1, LAG-3 mAb 2, LAG-3 mAb 4, LAG-3 mAb 5, and LAG-3 mAb 6, and to humanized and chimeric versions of such antibodies. The invention additionally pertains to LAG-3-binding molecules that comprise LAG-3 binding fragments of such anti-LAG-3 antibodies, immunoconjugates, and to bispecific molecules, including diabodies, BiTEs, bispecific antibodies, etc., that comprise (i) such LAG-3-binding fragments, and (ii) a domain capable of binding an epitope of a molecule involved in regulating an immune check point present on the surface of an immune cell. The present invention also pertains to methods of detecting LAG-3, as well as methods of using molecules that bind LAG-3 for stimulating immune responses.
Core Innovation
The disclosed invention relates to LAG-3-binding Fc-containing antibodies or Fc-containing molecules comprising an Fc region with engineered Fc variants for modulating FcγR binding. The engineered Fc region is configured to change binding to FcγR receptors, including FcγRIIB, and FcγR receptors associated with activating effector function, such as FcγRIIA, FcγRIIIA (CD16a), FcγRIIIB (CD16b), and FcγRIA (CD64). The Fc variant is described as providing a profile of altered FcγR binding, including cases where FcγR binding is not detectable.
The disclosure further describes using the altered FcγR binding profile to modulate effector function associated with Fcγ receptors, including ADCC and other Fc-mediated effector functions. In this context, the patent describes assay concepts for measuring altered FcγR binding and effector function for Fc variants. The engineered Fc variants include alterations based on an activating-to-inhibitory FcγR affinity ratio, including Fc variants that are described as enhancing effector function.
The disclosure additionally includes Fc region engineering for serum half-life extension, including preferred mutations for improving FcRn binding, and options across IgG isotypes and Fc region formats. The patent discusses IgG hinge and IgG2/IgG4 options with stabilizing hinge, Fc glycosylation site engineering and shifting, and transition into Fc region formats such as bispecific LAG-3-binding diabodies and trivalent Fc-containing molecules.
Claims Coverage
The consolidated claim coverage centers on a method of stimulating a T-cell-mediated immune response using a LAG-3-binding molecule that binds both human and cynomolgus monkey LAG-3, with the molecule defined by specific heavy- and light-chain variable domains and CDR sequences. Additional claim scope also covers Fc-containing LAG-3-binding molecules with engineered Fc variants for altered FcγR binding, effector function modulation, and serum half-life extension.
Cross-species LAG-3 binding for T-cell stimulation
Administering a therapeutically effective amount of a Lymphocyte Activation Gene 3 (LAG-3)-binding molecule capable of binding both human LAG-3 and cynomolgus monkey LAG-3, for stimulating a T-cell-mediated immune response in a subject.
Specified heavy- and light-chain CDR-defined variable domains
Employing a LAG-3-binding molecule comprising a Variable Heavy Chain Domain and a Variable Light Chain Domain, where the Variable Heavy Chain Domain includes CDR H1, CDR H2, and CDR H3 domains and the Variable Light Chain Domain includes CDR L1, CDR L2, and CDR L3 domains, with the CDR domains having amino acid sequences defined by SEQ ID NO values.
Variant Fc region with altered FcγR binding and serum half-life
In an Fc-containing embodiment, defining the molecule as including an Fc region that is a variant Fc region containing specified amino-acid substitutions, with Kabat EU numbering, configured to reduce binding affinity to an FcγR and/or enhance serum half-life.
Engineered Fc region for FcγR modulation
Providing an Fc region with engineered Fc variants configured to change binding to FcγR receptors, including FcγRIIB and FcγR receptors associated with activating effector function, such as FcγRIIA, FcγRIIIA (CD16a), FcγRIIIB (CD16b), and FcγRIA (CD64).
Altered FcγR binding profile for effector function modulation
Using an altered FcγR binding profile to modulate effector function associated with Fcγ receptors, including ADCC and other Fc-mediated effector functions, including Fc variants described as enhancing effector function.
Serum half-life extension by Fc engineering
Including Fc region engineering for serum half-life extension, including preferred mutations for improving FcRn binding, with options across IgG isotypes and Fc region formats.
The consolidated claims emphasize LAG-3-binding molecules defined by specific variable-domain CDR sequences, together with Fc engineering that alters FcγR binding, modulates effector function, and can extend serum half-life.
Stated Advantages
Stimulating a T-cell immune response in a subject.
Reducing FcγR binding affinity and/or enhancing serum half-life.
Providing a profile of altered FcγR binding, including cases where FcγR binding is not detectable.
Modulating effector function associated with Fcγ receptors, including ADCC and other Fc-mediated effector functions.
Enhancing effector function.
Extending serum half-life.
Documented Applications
Treating/diagnosing/prognosing diseases associated with suppressed immunity, particularly cancer, where T-cell-mediated immune response stimulation is described as the purpose of administration.
Detection uses are mentioned in the provided patent excerpt.
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