Covalent Heterobivalent Inhibitors for Drug Allergies

Drug allergies are a growing problem in the world today that accounts for over half of the allergy fatalities that occur each year. Patients in already compromised states in hospitals, either from infection, cancer or other disease, are particularly at risk. Often, while drug allergies may not cause fatal reactions, the presence of moderate reactions compels physicians to alter treatment regiments and compromise patient care. In particular, this is a major concern for cancer chemotherapeutics, where drug allergy rates can be as high as 20%. These immediate hypersensitivity reactions are triggered when drug specific immunoglobulin E (IgE) molecules bind drug labeled serum proteins (allergen) and trigger immune responses. In an effort to prevent these reactions, we have developed a specific inhibitor molecule, covalent heterobivalent inhibitors (cHBIs), that can disrupt the allergen-IgE interaction by specifically and permantely binding the IgE antigen binding site. By only targeting allergen specific IgEs through bivalent binding and subsequent covalent inhibition, cHBIs offer potent and long lasting inhibition of allergic reactions to any drug molecule. To date, we have engineered cHBIs to an antibiotic, penicillin G, and a common chemotherapeutic, oxaliplatin, representing both of the major classes of drug allergies. We demonstrate cHBI’s selective IgE targeting and in vitro and in vivo efficacy for preventing allergic reactions to both penicillin G and oxaliplatin. While, these two cHBI formulations are clinically viable treatments for very common drug allergies, this study also reveals the utility of the cHBI design, which can be adapted to any drug allergy.