Severe COVID-19 patients who develop acute respiratory distress syndrome (ARDS) and multiple organ failures share a hyperinflammatory cytokine/chemokine expression profile. This clinical observation resembles the cytokine releasesyndrome (CRS) which was the leading cause of mortality in patients infected with SARS-CoV and MERS-CoV. US FDAhave fast-tracked dozens of clinical trials to evaluate the efficacy of cytokine blockade therapies in the management ofCOVID-19 associated CRS. However, recent data released from majority of the trials indicated that blockade of onecytokine or Janus Kinase only marginally benefited patients regarding recovery time, and yet barely improved the mortalityrate compared with that of standard care. Therefore, it is urgently needed that a preclinical evaluation tool available to themedical researcher and pharmaceutical companies that could help them identify the most effective combinations oftherapeutic targets in the treatment of CRS. We propose to construct a single domain antibody (sdAb) library that containsa panel of sdAbs against clinically-characterized, significantly elevated cytokines and chemokines associated with COVID-19 CRS. This library could be harnessed as a tool to compare and contrast the potency of different cytokine/chemokineblockade therapy in a humanized PBMC engrafted CRS mouse model. Moreover, the library allows the testing ofsimultaneous blockade of multiple cytokine/chemokines as a combinatorial therapy for the treatment of CRS which ishypothesized to be resolution to the issue. To accomplish this in a prompt way, the modality of the library will be sdAb-encodings mRNA which is encapsulated in lipid nanoparticle (LNP) to avoid the hassle with the protein production andformulation. OncoTrap will leverage the expertise in in vitro antibody screening and molecular evolution platform, as wellas the lipid nanoparticle-based gene delivery system, which will be achieved in three specific aims. Aim 1 is intended toscreen the sdAbs against the designated cytokine or chemokine with each of them shows nanomolar or sub-nanomolarbinding affinity toward its target. Aim 2 is intend to characterize the PK profiles of sdAbs when they are delivered in theform of mRNA by LNP in vivo. In Aim 3, two representative sdAbs in the library will be tested in human PBMC engraftedCRS mouse model as the proof of concept study. Achievement of NIH-STTR phase I study will prepare the library forlarge-scale and systemic screening in the phase II, where the most effective therapeutics target(s) in the treatment of CRSwill be identified.
Public Health Relevance Statement: Project Narrative This project aims to develop a panel of human single-domain antibodies (sdAb) that potently and specifically neutralize the cytokines and chemokines clinically-implicated in the COVID-19 associated cytokine release syndrome (CRS). The resulting cyo/chemokine-specific sdAbs will be harnessed as a powerful and ready-to-use tool box to identify the most effective therapeutic intervention strategies for the treatment of various CRS-related human indications.
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