Covalent heterobivalent antibody inhibitors and ligands
Inventors
Bilgicer, Zihni Basar • DEAK, Peter Edward • Kiziltepe Bilgicer, Tanyel • Handlogten, Michael William • Ashley, Jonathan Darryl
Assignees
Publication Number
US-12018092-B2
Publication Date
2024-06-25
Expiration Date
2036-12-19
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Abstract
The invention provides a strategy for site specific covalent modification of antibodies using a specialized targeting covalent heterobivalent ligand (cHBL), and corresponding design for a covalent heterobivalent inhibitor (cHBI) that can be used to prevent Immunoglobulin E (IgE) mediated allergic reactions triggered by drug molecules, according to one embodiment. These molecules contain four important components: (1) an IgE antigen binding site (ABS) ligand that can be a mimotope for the allergen protein, a small molecule, or a peptidomimetic, (2) an appropriate linker, which can be any flexible or rigid chemical linker, providing spacing between the ABS binder and the other moieties, (3) a nucleotide binding site (NBS) ligand, and (4) a reactive moiety to form a covalent link with an amino acid side chain of target IgE antibodies.
Core Innovation
The invention provides a strategy for site-specific covalent modification of antibodies using specialized targeting molecules known as covalent heterobivalent ligands (cHBLs) and corresponding designs for covalent heterobivalent inhibitors (cHBIs). These molecules are structured with four critical components: an IgE antigen binding site (ABS) ligand, a chemical linker, a nucleotide binding site (NBS) ligand, and a reactive moiety that forms a covalent bond with amino acid side chains on target IgE antibodies. The cHBI concept leverages bivalent binding by targeting both the ABS and the conserved NBS on immunoglobulins, thereby increasing the effective local concentration of the reactive group and enabling selective, site-directed covalent inhibition of allergen-reactive antibodies.
The primary problem addressed is the need for selective, site-specific covalent modification of antibodies—especially IgE—to both facilitate robust antibody research and provide preventive or therapeutic interventions for IgE-mediated hypersensitivity and allergic reactions. Current methods for antibody-drug conjugation often require cumbersome ex vivo genetic modifications or lack specificity, and existing allergy treatments are unable to preemptively or selectively block anaphylactic reactions, particularly those triggered by drugs.
The disclosed cHBI molecules irreversibly inhibit allergen-reactive IgEs by covalently linking to an amino acid near the NBS after bivalent engagement at both the ABS and NBS. This action blocks antigen binding and crosslinking, thereby preventing mast cell and basophil degranulation. The design is extensible to a broad array of allergens, including food and drugs such as penicillin or peanut proteins, by modifying the ABS-binding component, and is applicable for in vitro antibody labeling as well as in vivo therapeutic or preventive interventions.
Claims Coverage
The patent includes three primary inventive features as exemplified by its independent claims.
Method of inhibiting or reducing the severity of allergic response using a covalent heterobivalent inhibitor
A method of inhibiting or reducing the severity of an allergic response to a peanut allergy or a penicillin allergy comprising: - Administering an effective amount of an inhibitor according to Formula III to a subject - The inhibitor binds immunoglobulin antibody to the allergen to prevent degranulation of mast cells and basophils - This method is applicable when administered prior to, after, during exposure to the allergen, or before immunotherapy desensitization - The inhibitor has the structural features as defined by Formula III—including: a targeting moiety for the ABS (TM), an optional targeting ligand for the conserved NBS (TL), an optional reactive group (FG), and variable length spacers (EG1, optional EG2) with specified chemical structures
Peanut allergy-specific inhibition using defined epitope sequences
A method for inhibiting or reducing the severity of a peanut allergic reaction by: - Administering an effective amount of an inhibitor according to Formula III to a subject - The targeting moiety (TM) includes one or more specified Ara h 2 or Ara h 6 allergen protein epitopes (SEQ ID NO: 6, 7, 9, 17, 18, 19, 27) - Other features as structurally defined in Formula III, including options for the reactive functional group (isothiocyanate), the NBS ligand (2-napthaleneacetic acid or indole-3-butyric acid), and a tag as a chromophore or fluorophore (such as dansyl or dinitrophenol)
Co-administration with epinephrine to mitigate anaphylaxis
The method allows for the co-administration of the covalent heterobivalent inhibitor with epinephrine: - Specifically mitigating an anaphylaxis response in a subject exposed to an allergen - The inhibitor structure and mode of action are as defined by Formula III
In summary, the claims encompass covalent heterobivalent inhibitors with defined modular structure for site-specific antibody modification and inhibition, methods of use for both peanut and penicillin allergy, including specific epitope targeting, and options for combination with standard anaphylaxis therapy.
Stated Advantages
Provides site-specific covalent modification of antibodies, enabling precise and selective targeting of allergen-reactive immunoglobulins.
Allows irreversible inhibition of allergen-reactive IgEs, effectively blocking antigen binding and preventing mast cell and basophil degranulation.
Functions as a potent and selective preventive or therapeutic approach for IgE-mediated allergic reactions, including rapid, preemptive, and post-exposure settings.
Versatile design enables adaptation to a wide variety of allergens or antibody targets by modifying the antigen binding site ligand.
The inhibitors demonstrate long-lasting effects, with inhibitory characteristics persisting for days in vitro.
Can be utilized for both scientific applications (site-specific antibody tagging in vitro) and therapeutic interventions in vivo.
Covalent binding selectivity is enhanced by bivalent binding, reducing off-target conjugation and allowing effective use in complex biological environments.
Documented Applications
Preemptive treatment to prevent severe allergic reactions to drugs or foods by administering cHBI molecules orally or by injection.
Post-reaction emergency treatment to prevent or stop proliferation of anaphylactic reactions.
Combination therapy with allergy immunotherapy to enable desensitization in highly sensitive patients by inhibiting IgE-mediated responses.
In vitro antibody labeling and site-specific modification for research, diagnostics, or biosensing.
Quantitative analysis of immunoglobulin concentration, inhibitor design, and antibody structure/function using tagged inhibitors in assays such as ELISA or flow cytometry.
Co-administration with epinephrine to mitigate or control anaphylaxis in subjects exposed to allergens.
Potential modulation of T-cell or B-cell receptor expression for autoimmune disease treatment or research through synthesis of cHBIs targeting TCR/BCR.
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