Friday, May 9, 2025
5/9/2025
BI-FUNCTIONAL THERAPEUTICS FOR ALLERGY-BFTA - DESCRIPTION (provided by applicant): IgE-mediated allergic diseases, afflicting 25% of the US population, are manifested as allergic asthma, rhinitis, food allergy, atopic dermatitis, and anaphylaxis. In addition to symptomatic treatments with various classical pharmaceutical agents, there are two main modalities of therapeutic treatment targeting directly at IgE- mediated immune response: Allergen desensitization or specific immunotherapy (SIT) and anti-IgE passive antibody treatment or Xolair. Herein, we propose a pan-IgE therapeutics (PIT) based on recent laboratory observation in that the receptor-binding CH(2 and CH(3 linker loop (C(2-3L) of human IgE, spanning the (-barrel of GFP is, conformationally constrained. Further, antibodies directed to C(2-3L constrained within the (-barrel of GFP, inhibit IgE binding to Fc(RI( and prevent mast cell activation. This observation prompts the product concept of employing C2-3L-GFP as a pan-IgE therapeutics (PIT) in treating IgE-mediated allergic diseases. Bifunctional immunogenicity of C(2-3L-GFP is a prerequisite for activating both neutralizing antibodies to C(2-3L and helper T-cells to GFP scaffold. This prerequisite underlies effectiveness as well as safety of the drug substance PIT in that, (i) Immune complexes formed by IgE and anti-C(2-3L are safely sequestered from binding to Fc(RI( receptors on mast cells/basophils, and are removed from the circulation and mucosal compartments. (ii) Due to the evolutionary distance of jellyfish from the mammals, immunogenicity of GFP provides necessary helper effect without provoking antibodies reactive to vital mammalian host proteins. The overall goal of Research is to evaluate the mass unit (purity) and its biological equivalents of PIT (bioreactivities; strength/concentration), its safety (adverse effect, ADE), pharmacokinetics (distribution), and pharmacodynamics (efficacies/effectiveness) as the drug substance. Data from an appropriate tg animal model will be collected, analyzed, intended as a clinical surrogate. AIM 1. TO EVALUATE THE CHEMICAL MASS UNIT OF PIT AND BIOLOGICAL EQUIVALENCE Incremental quality is required throughout all phases of mass unit characterization for consistency, safety, potency and effectiveness of the drug substance of PIT. GFP exhibits salient thermostability (Tm at 82.6¿C by differential scanning calorimetry). Recombinant protein will be enriched via internal His-tag. Aggregated or denatured protein will be separated by sizing with S-200 HR column and Superdex 75, followed by mono-Q on difference of charge density and by chromatofocussing according to difference of isoelectric point. The drug material will then be analyzed by amino acid sequencing, CD, MS/MS, and NMR. The mass unit will be tested in mice and escaladed in another species, rats and/or monkey. AIM 2. TO EVALUATE THE SAFETY AND THERAPEUTIC PRECAUTION OF PIT Three safety standards of the drug substance PIT vs. the native GFP will be evaluated: duration of antibody response appropriate for the protective window, allergenicity, autocreativity. We will evaluate whether duration of anti-C(2-3L antibody responses following the last immunization of the PIT regimen via mucosal vs. systemic route may be within one to three months' protective window. Should antibody responses persist beyond six months after termination of PIT, we will re-evaluate dosages and the booster schedules. Levels of circulation immune complexes, anti-GFP IgE and autoimmune antibodies will be measured. AIM 3. TO EVALUATE PHARMACOKINETICS OF IGE CLEARANCE IN ANIMAL MODEL BY PIT IgE receptors contribute to sequestration and/ or turnover of IgE. A mouse model expressing human Fc(RI( tg is employed for studying clearance of passively transferred human IgE, administered intravenously or via the intranasal route in a bolus on day 7 after the last immunization of the PIT regimen via subcut vs. Mucosal route. Levels of free JW8 vs. anti-IgE/JW8 immune complexes in sera and the BAL fluid will be evaluated. Levels of circulating IgG and mucosal IgA anti-IgE antibodies will be measured by subclass-specific ELISA. Duration of protective anti-C(2-3L for further rounds of IgE clearance will be assessed by two consecutive monthly administrations of fresh human IgE. AIM4. TO EVALUATE THE PHARMACODYNAMICS OF PIT IN TRANSGENIC AND HUMAN MAST CELLS IN VITRO AND IN VIVO Protection of antisera or affinity pure anti-C(2-3L from different species will be tested on human Fc(RI(+ bone marrow-derived mast cells from tg mice, and human mast cells in vitro. Moreover, Fc(RI( tg mice will be employed for studying pharmacodynamic effect of PIT in attenuating the IgE-mediated inflammatory responses with regard to airway hyperreactivity (AHR), airway remodeling via changes of extracellular matrix (ECM) and contractile issues, and inflammatory cell infiltrate and cytokines. In conclusion, by targeting IgE constant regions, PIT regimens may alleviate IgE- mediated diseases by a myriad of allergens. It is possible that PIT as a single biologics may include therapeutic indications of numerous recombinant allergens catering for subsets of allergic patients. Data collected from this study may be employed in part of preparing IND to pertinent Office for review at CBER. PUBLIC HEALTH RELEVANCE: The Project of bi-functional pan-IgE therapeutics may yield a commercializable product for treating IgE-mediated allergic diseases of different indications.
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