Botulinum poisoning is a rare neurotoxin-mediated syndrome that results in progressive respiratory and muscular paralysis and leads to death if untreated. Aerosolized botulinum neurotoxins (BoNT) are particularly lethal and of major concern as potential biological weapons. Given this concern, the U.S. has stockpiled the only approved antidote for BoNT poisoning, BAT®, to be used in case of intentional or unintentional release of infectious BoNT. BAT® consists of a polyclonal mixture of antibodies against botulinum toxin types A-G that is derived from equine serum following a complicated and time-consuming manufacturing process. While effective in abstracting BoNT in circulation, BAT® is associated with a number of primary safety concerns that limit its use to patients with a confirmed botulism diagnosis. As the earliest symptoms of botulism poisoning are non-specific, BAT® treatment is often administered well into the disease course when many patients require additional aggressive supportive care measures such as mechanical ventilation for survival. As such, a next generation BoNT antitoxin that is human-compatible, confers protection against multiple serotypes, demonstrates rapid clearance of circulating toxin, and can be safely administered as an early intervention upon suspicion of BoNT exposure is critically needed to replace BAT®. To address this need, NightHawk Biosciences, Inc. (NHB) is developing a multivalent botulinum antitoxin product based on their novel Terminator technology, which sequesters target pathogens by binding them to circulating red blood cells (RBCs) via receptor type I (CR1) and delivers them to fixed-tissue macrophages for engulfment. To date, experimental results indicate that the Terminator system can be used to induce RBC immune adherence to effectively remove a variety of pathogens from circulation, drastically reducing the blood concentration of pathogenic particles within minutes of treatment. Critically, Terminator has demonstrated good safety and tolerability in humans, positioning it potentially as a drug of low regret that can be safely administered prior to clinical confirmation of diagnosis. In this Phase I SBIR, NHB will advance a Terminator BoNT antitoxin candidate consisting of a unique antibody complex in which a human CR1 antibody is fused to an antibody targeting the BoNT serotypes associated with human disease (A, B, E, and F). To adequately de-risk this candidate for IND-enabling studies, this proposal will 1) demonstrate selective and high- affinity cross-serotype binding and specific uptake into macrophages; 2) define the kinetics of Terminator- mediated clearance of BoNTs in vivo; and 3) demonstrate efficacy to protect against BoNT poisoning in a postexposure mouse model. Phase II studies will expand efficacy evaluations into aerosol challenge models and initiate IND-enabling toxicology and dose-refining studies.
Public Health Relevance Statement: PROJECT NARRATIVE Botulinum poisoning is a rare but lethal syndrome that results from neurotoxin-mediated respiratory and muscular paralysis. The only approved antidote suffers from high cost of goods and significant safety liabilities. NightHawk Biosciences, Inc. is developing a novel botulism antitoxin that rapidly binds and sequesters toxins in the bloodstream before delivering them directly to the liver or spleen for destruction. This next generation antitoxin candidate exhibits potential for rapid pathogen clearance and substantial improvements in manufacturing costs and safety over the currently fielded countermeasure.
Project Terms: abstracting; Acids; Aerosols; After Care; After-Treatment; post treatment; Aftercare; Antibodies; Theriacs; Antidotes; antitoxin; anti-toxin; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Bacteria; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Blood; Blood Reticuloendothelial System; Blood Circulation; Bloodstream; Botulinum Antitoxin; botulinum anti-toxin; Botulinum Toxin Type A; Botulinum A Toxin; Botulinum Neurotoxin A; Clostridium Botulinum Toxin Type A; Clostridium botulinum A Toxin; botulinum toxin A; Botulinum Toxins; Bontoxilysin; Botulin; Clostridium botulinum Toxins; botulinum neurotoxin; Botulism; Toxico-Infectious Botulism; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Clostridium botulinum; C botulinum; C. botulinum; Complement; Complement Proteins; Cessation of life; Death; Diagnosis; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Exhibits; Gram-Positive Bacteria; Equus caballus; Domestic Horse; Equine; Equine Species; Equus przewalskii; Horses; Human; Modern Man; Immediate hypersensitivity; Atopic Hypersensitivity; IgE-Mediated Hypersensitivity; Type I Hypersensitivity; humoral hypersensitivity; Immune Sera; Antisera; immune serum; In Vitro; Incidence; Kinetics; Libraries; Liver; hepatic body system; hepatic organ system; Macrophage; MÏ; Microspheres; Microbeads; mortality; Mus; Mice; Mice Mammals; Murine; Muscle; Muscle Tissue; muscular; Persons; Nerve Block; Neural Block; Neural Blockade; Neurotoxins; neurotoxicant; Patients; Poisoning; poisoned; Production; Proteins; Quality Control; Complement Receptor; Risk; Safety; Serotyping; Serum Sickness; Specificity; Spleen; Spleen Reticuloendothelial System; Syndrome; Technology; Time; Toxicology; Toxin; Virus; Measures; Regrets; Mediating; improved; mechanical respiratory assist; mechanically ventilated; Mechanical ventilation; Clinical; Phase; Variation; Variant; Link; Blood Serum; Serum; sugar; Early Intervention; uptake; Exposure to; Supportive care; Supportive Therapy; Intravenous; Hour; Immune; Immunes; Complex; intraperitoneal; Reaction; Source; System; respiratory; Paralysed; Palsy; Plegia; paralysis; paralytic; Infusion procedures; Infusion; infusions; particle; receptor; Receptor Protein; chimeric antibody; novel; Categories; Positioning Attribute; Position; Modeling; response; tissue fixing; Pathogenicity; Molecular Interaction; Binding; Address; Length; Dose; Symptoms; Adherence; Affinity; in vivo; Phage Display; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Monitor; cost; next generation; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; manufacturing process; botulinum; pathogen; Hu-mABs; humAbs; human mAbs; human monoclonals; human monoclonal antibodies; Consumption; human disease; murine model; mouse model; aerosolized; phase II study; phase 2 study; efficacy study; biological weapon; bioweapon; side effect; Circulation; manufacturing cost; fabrication cost
