grant

Multidimensional antibody engineering to enhance the potency and breadth of a betacoronavirus medical countermeasure

Organization EITR BIOLOGICS, INC.Location SAN DIEGO, UNITED STATESPosted 1 Jul 2023Deadline 31 Aug 2027
NIHUS FederalResearch GrantFY20252019 novel corona virus2019 novel coronavirus2019-nCoV2019-nCoV S protein2019-nCoV spike glycoprotein2019-nCoV spike protein2019-nCoV vaccine2019-nCoV variant2019-nCoV variant forms2019-nCoV variant strains7S Gamma GlobulinAccelerationAddressAffinityAntibodiesAntibody Binding SitesAntigenic DeterminantsAntigensAssayB blood cellsB cellB cellsB-CellsB-LymphocytesB-cellBi-specific antibodiesBifunctional AntibodiesBindingBinding DeterminantsBioassayBiological AgentBiological AssayBiological ProductsBispecific AntibodiesBlood SerumBody TissuesBovine SpeciesCHO CellsCOVID crisisCOVID epidemicCOVID pandemicCOVID-19COVID-19 S proteinCOVID-19 crisisCOVID-19 epidemicCOVID-19 eraCOVID-19 global health crisisCOVID-19 global pandemicCOVID-19 health crisisCOVID-19 pandemicCOVID-19 periodCOVID-19 public health crisisCOVID-19 spikeCOVID-19 spike glycoproteinCOVID-19 spike proteinCOVID-19 vaccineCOVID-19 variantCOVID-19 variant formsCOVID-19 variant strainsCOVID-19 virusCOVID-19 yearsCOVID19 virusCV-19CattleCell LineCellLineChinese Hamster OvaryChinese Hamster Ovary CellClinicalClinical Treatment MoabCoV S proteinCoV glycoprotein SCoV spike glycoproteinCoV spike proteinCoV-2CoV2Common Rat StrainsCoronavirus Infectious Disease 2019Coronavirus glycoprotein SCoronavirus spike proteinCricetinaeCustomDNA mutationDimensionsDoseDrug KineticsElderlyEpitopesEvaluationFormulationFutureGenerationsGenetic ChangeGenetic PolymorphismGenetic defectGenetic mutationGenetics-MutagenesisGlycoproteinsGoalsHalf-LifeHamstersHamsters MammalsHourIgGImmune responseImmunityImmunizeImmunocompromisedImmunocompromised HostImmunocompromised PatientImmunoglobulin GImmunosuppressed HostImmunotherapeutic agentIn vivo analysisIndividualInfectionLeadMAb TherapeuticsMERSMERS corona virusMERS coronavirusMERS coronavirus diseaseMERS virusMERS-CoVMERS-CoV diseaseMiddle East Respiratory SyndromeMiddle East Respiratory Syndrome CoV diseaseMiddle East Respiratory Syndrome Corona 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agentbovidbovinebsAbcoronavirus S proteincoronavirus disease 2019coronavirus disease 2019 S proteincoronavirus disease 2019 crisiscoronavirus disease 2019 epidemiccoronavirus disease 2019 global health crisiscoronavirus disease 2019 global pandemiccoronavirus disease 2019 health crisiscoronavirus disease 2019 pandemiccoronavirus disease 2019 public health crisiscoronavirus disease 2019 spike glycoproteincoronavirus disease 2019 spike proteincoronavirus disease 2019 vaccinecoronavirus disease 2019 variantcoronavirus disease 2019 variant formscoronavirus disease 2019 variant strainscoronavirus disease 2019 viruscoronavirus disease crisiscoronavirus disease epidemiccoronavirus disease pandemiccoronavirus disease-19coronavirus disease-19 global pandemiccoronavirus disease-19 pandemiccoronavirus disease-19 vaccinecoronavirus disease-19 viruscoronavirus infectious disease-19coronavirus spike glycoproteincowcross reactivitycultured cell linecustomsdisease severitygenome mutationgeriatricgroup competitionhCoV19heavy metal Pbheavy metal leadhigh risk grouphigh risk individualhigh risk peoplehigh risk populationhost responseimmune drugsimmune system responseimmune-based therapeuticsimmunogenimmunologic therapeuticsimmunoresponseimmunosuppressed patientimmunotherapeuticsimmunotherapy agentin vitro activityin vivoin vivo evaluationin vivo testinglead candidatemAbsmedical countermeasuremonoclonal Absmonoclonal antibody drugsnCoV vaccinenCoV-19 vaccinenCoV19 vaccinenCoV2namenamednamingnano-molarnanomolarnanotherapeuticnovelpandemicpandemic diseasepolymorphismpre-clinical developmentpreclinical developmentprophylacticresolutionsresponsescreeningscreeningssenior citizensevere acute respiratory syndrome coronavirus 2 global health crisissevere acute respiratory syndrome coronavirus 2 global pandemicsevere acute respiratory syndrome coronavirus 2 variantsevere acute respiratory syndrome coronavirus 2 variant formssevere acute respiratory syndrome coronavirus 2 variant strainssmall molecular inhibitorsmall molecule inhibitorspike proteins on SARS-CoV-2stemtechnology platformtechnology systemtherapeutic candidatetherapeutic mAbsvaccine against 2019-nCovvaccine against COVID-19vaccine against SARS-CoV-2vaccine against SARS-coronavirus-2vaccine against Severe Acute Respiratory Syndrome CoV 2vaccine against Severe acute respiratory syndrome coronavirus 2vaccine candidates against SARS-CoV-2vaccine failurevaccine for novel coronavirusvaccines preventing COVIDvaccines to prevent COVIDvariants of concernweaponsβ CoVβ coronavirusβCoV
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Full Description

The magnitude and duration of the ongoing COVID-19 pandemic have underscored the need to
have a well-equipped—and ideally prepositioned—arsenal of antiviral weapons to mount an
adequate public health response. A key lesson is that multiple medical countermeasures (MCMs)
are needed to maintain potency and efficacy in the face of a rapidly evolving virus. Several
approved SARS-CoV-2 vaccines have been paramount to gaining control over the pandemic,
reducing both the number of infections and severity of disease for much of the global population.
Unfortunately, these vaccines provide little to no protection to immunocompromised individuals
who are unable to mount an effective immune response. Half-life extended monoclonal antibodies
(mAbs) offer an attractive alternative, as their long half-life and high potency offer instantaneous
immunity and vaccine-like protection without requiring the generation of a robust immune
response. While >10,000 mAbs and multiple mAb cocktails have been explored over the course
of the pandemic and several advanced as therapeutic candidates, they have largely failed to
maintain potent activity in the face of prevalent antigenic drift within the SARS-CoV-2 spike
protein. Moreover, currently approved vaccines and immunotherapeutics offer no protection from
a related b-CoV, Middle East respiratory syndrome (MERS) virus. While small molecule inhibitors
such as Paxlovid have shown broad in vitro activity against SARS and MERS, significant issues
with COVID-19 rebound following treatment suggest it may not remain efficacious against the
more lethal MERS virus. A recently identified antibody, 1249A8 (renamed AR-703), that
recognizes a unique and highly conserved epitope in the S2 domain of the coronavirus spike
protein offers a potential solution, being refractory to antigenic drift and having broad activity b-
CoV activity, inclusive of SARS and MERS. The goal of the proposal is to maximize the clinical
utility of AR-703 through multidimensional structure-based approach to increase neutralization
potency and expand breadth of AR-703. In parallel, bispecific antibody engineering utilizing a
novel bovine ultra-long CDR3 (UL-CDR3) based bispecific platform technology will be explored
to introduce synergistic neutralization and resist viral escape. The structures of bovine UL-CDR3s
have a demonstrated ability to independently target cryptic highly conserved epitopes, vital to
maintaining efficacy to novel viral variants. Combining AR-703 and pan-b-CoV UL-CDR3 into a
single bispecific would enable dual engagement of highly conserved neutralizing epitopes offering
a potent solution to SARS2 antigenic drift for the immunocompromised while also guarding
against related lethal b-CoVs should they emerge in the future.

Grant Number: 4R44AI177179-02
NIH Institute/Center: NIH
Principal Investigator: Zachary Bornholdt

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