Document text
Principal Investigator: Xiang Gao
Organization: ONCOTRAP, INC.
Fiscal Year: 2022
Award: $299,128
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
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 release
syndrome (CRS) which was the leading cause of mortality in patients infected with SARS-CoV and MERS-CoV. US FDA
have fast-tracked dozens of clinical trials to evaluate the efficacy of cytokine blockade therapies in the management of
COVID-19 associated CRS. However, recent data released from majority of the trials indicated that blockade of one
cytokine or Janus Kinase only marginally benefited patients regarding recovery time, and yet barely improved the mortality
rate compared with that of standard care. Therefore, it is urgently needed that a preclinical evaluation tool available to the
medical researcher and pharmaceutical companies that could help them identify the most effective combinations of
therapeutic targets in the treatment of CRS. We propose to construct a single domain antibody (sdAb) library that contains
a 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/chemokine
blockade therapy in a humanized PBMC engrafted CRS mouse model. Moreover, the library allows the testing of
simultaneous blockade of multiple cytokine/chemokines as a combinatorial therapy for the treatment of CRS which is
hypothesized 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 and
formulation. OncoTrap will leverage the expertise in in vitro antibody screening and molecular evolution platform, as well
as the lipid nanoparticle-based gene delivery system, which will be achieved in three specific aims. Aim 1 is intended to
screen the sdAbs against the designated cytokine or chemokine with each of them shows nanomolar or sub-nanomolar
binding affinity toward its target. Aim 2 is intend to characterize the PK profiles of sdAbs when they are delivered in the
form of mRNA by LNP in vivo. In Aim 3, two representative sdAbs in the library will be tested in human PBMC engrafted
CRS mouse model as the proof of concept study. Achievement of NIH-STTR phase I study will prepare the library for
large-scale and systemic screening in the phase II, where the most effective therapeutics target(s) in the treatment of CRS
will be identified.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ARDS><Achievement><Achievement Attainment><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B.1.1.7><B.1.351><BCDF><BSF-2><BSF2><Back><Bacterial Infections><Beta Proprotein Interleukin 1><Binding><Biological><Brazil><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 immunity><COVID-19 infected patient><COVID-19 outbreak><COVID-19 patient><COVID-19 positive patient><COVID-19 therapy><COVID-19 treatment><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19><COVID19 immunity><COVID19 outbreak><COVID19 patient><COVID19 positive patient><COVID19 therapy><COVID19 treatment><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cachectin><Cause of Death><Cell Communication and Signaling><Cell Signaling><Chemotactic Cytokines><Clinical><Clinical Data><Clinical Trials><CoV-2><CoV2><Combined Modality Therapy><Da Nang Lung><Data><Development><Directed Molecular Evolution><Dorsum><Dose><Drops><Encapsulated><Ensure><Feedback><Fever><Formulation><Future><GM-CSF><Gamma interferon><Genetic Alteration><Genetic Change><Genetic defect><Granulocyte-Macrophage Colony-Stimulating Factor><HPGF><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepatocyte-Stimulating Factor><Histamine-Producing Cell-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Evasion><Immune Interferon><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><In Vitro><Intercrines><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intravenous><Investigators><JAK kinase><Janus kinase><Lead><Libraries><Liver><Liver Cells><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><MGI-2><MOF syndrome><Macrophage-Derived TNF><Medical><Messenger RNA><Mice><Mice Mammals><Microfluidics><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modality><Modeling><Modern Man><Molecular Evolution><Molecular Interaction><Molgramostin><Monocyte-Derived TNF><Multimodal Therapy><Multimodal Treatment><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Mutation><Myeloid Differentiation-Inducing Protein><NIH><National Institutes of Health><PBMC><Patients><Pb element><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Phase 3 Clinical Trials><Phase I Study><Phase III Clinical Trials><Plasmacytoma Growth Factor><Preinterleukin 1 Beta><Process><Production><Proteins><Protocol><Protocols documentation><Pyrexia><Reaction><Reagent><Recovery><Research Personnel><Research Resources><Researchers><Resolution><Resources><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 B.1.1.7><SARS-CoV-2 B.1.351><SARS-CoV-2 alpha><SARS-CoV-2 beta><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 outbreak><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 outbreak><SARS-CoV2 vaccine><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SBIR><SIS cytokines><STTR><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Innovation Research><Small Business Innovation Research Grant><Small Business Technology Transfer Research><South Africa strain><South Africa variant><South African strain><South African variant><Specificity><Stiff lung><Surface><Symptoms><System><TC-GM-CSF><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Time><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Cell Human GM Colony-Stimulating Factor><U.K. variant><UK strain><UK variant><Uncertainty><United Kingdom variant><United States National Institutes of Health><Vaccines><Validation><Variant><Variation><Viral><Viral Diseases><Virus Diseases><Wuhan coronavirus><Yeasts><bacteria infection><bacterial disease><biologic><biological signal transduction><chemoattractant cytokine><chemokine><clinical relevance><clinically relevant><combination therapy><combinatorial><combined modality treatment><combined treatment><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 outbreak><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 outbreak><coronavirus disease-19 patient><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><cytopenia><design><designing><developmental><directed evolution><disease severity><dosage><doubt><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><febrile><febris><gene delivery system><genome mutation><granulocyte macrophage colony stimulating factor><hCoV19><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><immunity against COVID-19><immunity against COVID19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to COVID19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><improved><in vivo><inhibitor><inpatient care><inpatient service><interferon beta 2><interventional strategy><lFN-Gamma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><model of animal><model organism><mortality><mouse model><multi-modal therapy><multi-modal treatment><multiorgan failure><multiple organ system failure><murine model><nCoV2><nano particle delivery><nano-molar><nanobodies><nanobody><nanomolar><nanoparticle delivered><nanoparticle delivery><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><phase 1 study><phase 2 study><phase II study><phase III protocol><pre-clinical><pre-clinical evaluation><preclinical><preclinical evaluation><primary end point><primary endpoint><respiratory><screening><sdAb><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 B.1.1.7><severe acute respiratory syndrome coronavirus 2 B.1.351><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single domain antibodies><standard care><standard treatment><therapeutic target><therapeutically effective><tool><translational study><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment strategy><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><viral infection><virus infection><virus-induced disease><wet lung><µfluidic>