The Department of Defense (DOD) is seeking innovative solutions through the Small Business Innovation Research (SBIR) program to develop prophylactics and therapeutics for neurotoxin exposure, specifically targeting organophosphorus compounds used in chemical warfare. The objective is to create a biological agent that can prevent illness from exposure to G-type and V-type nerve agents, with a focus on stability, efficacy, and pharmacokinetics for both prophylactic and therapeutic applications. This initiative is crucial for enhancing the safety of military personnel on the battlefield and protecting civilians from potential chemical attacks. Interested parties should note that the solicitation will open on January 29, 2025, and close on February 26, 2025, with further details available at the DOD SBIR website.

## Description

The primary problem this topic addresses are gaps in our ability to sustain troops on the battleﬁeld under exposure to chemical weapons. Furthermore, chemical attacks on the homeland would place U.S. civilians in harm&rsquo;s way without an effective remedy. Organophosphorus compounds pose signiﬁcant threats to military personnel. At lethal doses these agents act irreversibly on the nervous system, resulting in uncontrolled convulsions followed by rapid death. Butyrlcholinesterase is human enzyme that stoichometrically binds these compounds and prevents them from reaching their physiological targets. However, when produced endogenously, these large enzymes are difficult to prophylactically deliver in sufficient doses to mitigate expected organophosphorus compound exposure. Human Paraoxonase has been demonstrated to detoxify organophosphorus compounds. Phosphotriesterases (PTEs) and Organophosphate Acid Anhydrolase (OPAA) are enzymes that neutralize G-type nerve agents both environmentally and in the human body. Mutant PTE has even been developed for detoxification of the highly toxic V-type agents. Biodistribution proﬁles and protease susceptibility characteristics have prevented these enzyme-classes from employment as prophylactic agents or as post-exposure therapeutics. This topic solicits innovative chemistries and approaches to render such enzymes stable in circulating blood over for up to several months and at sufficient levels to mitigate exposure to operationally relevant quantities of organophosphorus compounds while also considering biodistribution, toxicity, and clearance. Prophylactic and therapeutic doses of protected OPAA and PTE would ideally be injected intramuscularly or subcutaneously to rapidly neutralize nerve agents in vivo and minimize acute and chronic injuries. A prophylactic and therapeutic chemical medical countermeasure comprised of human-compatible formulations containing neuro-protective enzymes would enable military and ultimately civilian use for protection against nerve agents in combat scenarios and therapeutic treatment in combat and non-combat scenarios.

## Objective

A biological agent is sought to prevent illness upon exposure to chemical warfare nerve agents, to include G-type or V- type neurotoxins, by either administering a prophylactic before anticipated exposure or administering a therapeutic after symptoms of exposure. Phase II will demonstrate robust deactivation of neurotoxins in vitro with foundational studies targeting appropriate efficacy and pharmacokinetics to include physiological half-life, clearance, and tolerance.

## Phase I

Phase I will demonstrate ability to perform assays probing PTE and/or OPAA turnover rates for chemical reactions on model compounds that mimic deactivation of a multiple nerve agents. The studies will characterize catalyst performance under various destabilizing environments such as thermal and chemical denaturing conditions comparing wild-type enzyme and enzyme with some degree of stabilization chemistry employed. A target is demonstrating turnover rates for stabilized enzyme that approach wild-type values. Phase I will provide a plan for access to multiple classes of nerve agents and the ability to work with these samples which may involve exploiting or establishing an enabling collaboration with a partner having these abilities.

## Phase II

Phase II will deliver prototype MCMs wherein the enzyme has been demonstrated to retain catalytic activity after being stabilized against various denaturing conditions. The delivered compounds, produced in mg quantities, will be characterized for deactivation of multiple classes of nerve agents under chemical and biochemical conditions comparable to physiological exposure. Turnover rates and lifetimes will be rigorously documented for each compound for multiple nerve agents. Top candidate drugs/biological agents emerging from these systematic studies will be bolstered to increase performance in both activity and stability. Ultimately at the end of Phase II, mg quantities of the best performing compounds will be delivered for Phase III animal studies.

## Phase III: Dual Use Applications

PHASE III: The goal of Phase III work will be to evaluate the protective formulations for the peripheral and central nervous systems though animal studies. Evaluating how the compounds distribute throughout the body, accumulate in speciﬁc tissues, and are cleared will enables the reﬁnement of further design to enhance stability, prolong circulation time, and catalysts compounds remain active for longer durations. Ultimately, Phase III will pursue (1) intramuscular administration with (2) peripheral and central nervous system entry and (3) long duration of circulation and enzyme activity. Higher animal models beyond mice and towards enabling human clinical trials is a goal of Phase III.PHASE III DUAL USE APPLICATIONS: The delivered therapeutic will allow medical intervention for the domestic public that would be needed after a domestic involving G-type nerve agents or during an organophosphorus insecticide accidental spill or exposure. The treatment would also be available for CONUS troops.

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