Project Grant R44AI147898

DEVELOPMENT OF WORLD'S FIRST FULLY HUMAN BROAD SPECTRUM ANTI-SNAKE VENOM - ABSTRACT SNAKEBITE ENVENOMING POSES A GLOBAL RISK TO HUMAN HEALTH. FOR OVER 125 YEARS, ANTIVENOMS HAVE CONSISTED OF ANIMAL-DERIVED POLYCLONAL SERUM IMMUNOGLOBULIN G (IGG). IN RECENT DECADES, IGG DIGESTED INTO ANTIGEN-BINDING FRAGMENTS FAB(2) HAS BEEN FOUND TO REDUCE SOME OF THE MOST SEVERE SIDE-EFFECTS OF NON-HUMAN ANTIVENOM. THESE ANTIVENOMS ARE OBTAINED BY IMMUNIZING HORSES OR SHEEP WITH INDIVIDUAL SNAKE VENOM, IN ORDER TO PRODUCE A PRODUCT THAT IS EFFECTIVE ONLY AGAINST THOSE SPECIFIC SNAKE SPECIES. THERE ARE CURRENTLY OVER 40 ANTIVENOM PRODUCTS AGAINST INDIVIDUAL SNAKE SPECIES, AND THESE TREATMENTS ALL PRESENT SEVERAL CHALLENGES, INCLUDING EARLY- ONSET ADVERSE REACTIONS TO ANIMAL PLASMA DERIVED ANTIVENOMS, SHORTENED HALF-LIFE, NEED FOR REPEATED INTRAVENOUS (IV) INFUSION BY MEDICAL PERSONNEL, AND CORRECT IDENTIFICATION OF THE SPECIFIC SNAKE. IN CONTRAST, HUMAN RECOMBINANT BROADLY NEUTRALIZING ANTIBODIES (BNABS) CAPABLE OF RECOGNIZING SHARED TOXINS FOUND ACROSS ALL SNAKE VENOMS WOULD ENABLE THE PRODUCTION OF A SINGLE BROAD-SPECTRUM PRODUCT TO TREAT ALL SNAKEBITE. HUMAN IGG BNABS WOULD AVOID THE SERUM SICKNESS AND ANAPHYLAXIS RISK INHERENT TO NON-HUMAN ANTIVENOM, MAKING POSSIBLE SAFE USE OF INTRAMUSCULAR (IM) DELIVERY AND FIELD DEPLOYMENT OF A FULL IGG PRODUCT WITH A 3-WEEK HALF-LIFE. WE WILL EXTEND OUR WORK FROM THE PHASE I, WHERE FULLY-HUMAN, BNABS IDENTIFIED FROM A UNIQUE ANTIBODY REPERTOIRE WERE CHARACTERIZED AND VALIDATED TO HAVE BROAD IN VIVO EFFICACY. NOW, CENTIVAX WILL COMPLETE THE DISCOVERY OF BNABS AGAINST THE REMAINING KEY TOXINS COMMON TO ALL SNAKE VENOM, FOR THE DEVELOPMENT OF VENPEN, A BROAD-SPECTRUM, THERMOSTABILIZED, LYOPHILIZED, FULLY HUMAN-DERIVED ANTIVENOM, WITH REDUCED NEED FOR REFRIGERATION OR TRAINING AND CAPABLE OF IM DELIVERY A FIELD-DEPLOYABLE DUAL-CHAMBER INJECTOR. UNIQUELY, THESE ANTIBODIES WERE ISOLATED FROM A UNIQUE HYPER-IMMUNE SUBJECT WHOSE IMMUNE SYSTEM HAS DEVELOPED BROADLY NEUTRALIZING, HIGHLY-SPECIALIZED ANTI-SNAKE VENOM ANTIBODIES THROUGH A HISTORY OF DOCUMENTED ESCALATING DOSE SELF-IMMUNIZATIONS OVER 17+ YEARS WITH DIVERSE SNAKE VENOMS. CENTIVAX IS WELL ON THE WAY TO DEVELOPING VENPEN UNIVERSAL ANTIVENOM, WITH ONE BROADLY-NEUTRALIZING IN VIVO PROTECTIVE ANTIBODY TO LONG-NEUROTOXINS ALREADY DEVELOPED AND BNABS TO THE OTHER FOUR MOST DANGEROUS TOXINS IN VARIOUS STAGES OF DEVELOPMENT. AIM 1: COMPLETE THE DEVELOPMENT OF THE ELAPID COCKTAIL BY IDENTIFYING BNABS AGAINST THE REMAINING DOMINANT TOXINS IN THE ELAPIDAE SNAKE FAMILY AND DEMONSTRATE PROTECTION IN VIVO AGAINST WHOLE VENOM OF DIVERSE ELAPID SNAKE GENERA OF MEDICAL CONSEQUENCE. AIM 2: COMPLETE THE DEVELOPMENT OF IDENTIFYING BNABS AGAINST DOMINANT TOXINS IN THE VIPERIDAE FAMILY, AND CHARACTERIZE THE PROTECTION IN VIVO AGAINST DIVERSE GENERA OF VIPERIDS OF MEDICAL CONSEQUENCE. AIM 3: COMBINE AND FORMULATE THE FINAL VENPEN BNAB COCKTAIL FOR LYOPHILIZATION FOR USE IN BOTH IV VIALS AS WELL AS RAPID IM DELIVERY DUAL CHAMBER AUTO-INJECTOR. THE POTENTIAL BENEFITS AND APPLICATIONS OF A THERMOSTABILIZED, BROADLY NEUTRALIZING ANTI-VENOM ARE FAR REACHING INCLUDING MAXIMIZING PROTECTION OF ALL AMERICANS EXPOSED TO SNAKEBITE, U.S. MILITARY PERSONNEL DEPLOYED BOTH NATIONALLY AND ABROAD, AND RURAL COMMUNITIES WORLDWIDE.