Preclinial Safety and Efficacy of a Therapeutic Antibody That Targets SARS-CoV-2 at the Sotrovimab Face But is Escaped by Omicron DOI
Jakob Kreye, S. Momsen Reincke,

Stefan Edelburg

et al.

SSRN Electronic Journal, Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 1, 2022

The recurrent emerging of novel viral variants concern (VOCs) with evasion preexisting antibody immunity upholds SARS-CoV-2 case numbers and maintain a persistent demand for updated therapies. We selected the patient-derived CV38-142 based on its potency breadth against VOCs Alpha, Beta, Gamma Delta preclinical development into therapeutic. showed in vivo efficacy Syrian hamster VOC infection model after post-exposure therapeutic application revealed favorable safety profile human protein library screen tissue cross-reactivity study. Although targets same surface as Sotrovimab which maintains activity Omicron, did not neutralize Omicron lineages BA.1 BA.2. These results highlight contingencies developing therapeutics context antigenic drift reinforce need to develop broadly neutralizing variant-proof antibodies SARS-CoV-2.Funding Information: This work was supported by German Research Foundation (DFG) (grants FOR3004, PR1274/3-1 PR1274/5- 1 H.P.; project 184695641 – SFB 958, 327654276 1315 under Germany’s Excellence Strategy Exc-2049-390688087 D.S.), Helmholtz Association (HIL-A03 H.P.), Federal Ministry Education (Connect-Generate 01GM1908D H.P) European Council (ERC) Union’s Horizon 2020 research innovation programme (Grant agreement No. 810580 D.S.).Declaration Interests: Center Neurodegenerative Diseases (DZNE) Charité-Universitätsmedizin Berlin have filed patent (application number: PCT/EP2021/064352) treatment J.K., S.M.R., H.-C.K., E.S.-S., L.E.S., V.M.C. H.P. are named inventors. is together Euroimmun GmbH recently regarding diagnostic testing. S.E., V.N., M.M., S.K., S.H., P.H. U.J. employees Miltenyi Biotec B.V. & Co. All other authors declare no competing interests.Ethics Approval Statement: animal experiment approved Landesamt für Gesundheit und Soziales Berlin, Germany (approval number 0086/20) performed compliance relevant national international guidelines care humane use animals.

Language: Английский

Emerging SARS-CoV-2 variants of concern evade humoral immune responses from infection and vaccination DOI Creative Commons
Tom G. Caniels, Ilja Bontjer, Karlijn van der Straten

et al.

Science Advances, Journal Year: 2021, Volume and Issue: 7(36)

Published: Sept. 3, 2021

Antibodies of convalescent COVID-19 patients and vaccine recipients show reduced recognition SARS-CoV-2 variants concern.

Language: Английский

Citations

100
Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants DOI Creative Commons
Meng Yuan, Deli Huang, Chang‐Chun D. Lee

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Feb. 17, 2021

Abstract The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised emergence the recent variants. Residues E484 K417 in receptor-binding site (RBS) are both mutated lineages first described South Africa (B.1.351) Brazil (B.1.1.28.1). nAbs isolated from patients preferentially encoded certain heavy-chain germline genes two most frequently antibody families (IGHV3-53/3-66 IGHV1-2) can each bind RBS different binding modes. However, their neutralization abrogated either E484K or K417N mutation, whereas to cross-reactive CR3022 S309 sites largely unaffected. This structural functional analysis illustrates why mutations at adversely affect major classes consequences for next-generation COVID-19 vaccines.

Language: Английский

Citations

56
Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics DOI Creative Commons
Lennox Chitsike, Penelope J. Duerksen-Hughes

Virology Journal, Journal Year: 2021, Volume and Issue: 18(1)

Published: July 23, 2021

The COVID-19 pandemic has put healthcare infrastructures and our social economic lives under unprecedented strain. Effective solutions are needed to end the while significantly lessening its further impact on mortality life. widely-available vaccines have appropriately long been seen as best way pandemic. Indeed, current availability of several effective already making a significant progress towards achieving that goal. Nevertheless, concerns risen due new SARS-CoV-2 variants harbor mutations against which less effective. Furthermore, some individuals unwilling or unable take vaccine. As health officials across globe scramble vaccinate their populations reach herd immunity, challenges noted above indicate therapeutics still work alongside vaccines. Here we describe neutralizing antibodies had those with early mild COVID-19, what approval for management means other viral entry inhibitors similar mechanism action. Importantly, also highlight studies show therapeutic strategies involving various such multivalent antibodies, recombinant ACE2 miniproteins can be not only pre-exposure prophylaxis, but in protecting antigenic drift future zoonotic sarbecoviruses.

Language: Английский

Citations

42
Emerging SARS-CoV-2 variants of concern evade humoral immune responses from infection and vaccination DOI Open Access
Tom G. Caniels, Ilja Bontjer, Karlijn van der Straten

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: June 1, 2021

Emerging SARS-CoV-2 variants pose a threat to human immunity induced by natural infection and vaccination. We assessed the recognition of three concern (B.1.1.7, B.1.351 P.1) in cohorts COVID-19 patients ranging disease severity (n = 69) recipients Pfizer/BioNTech vaccine 50). Spike binding neutralization against all VOC was substantially reduced majority samples, with largest 4-7-fold reduction being observed B.1.351. While hospitalized vaccinees maintained sufficient neutralizing titers VOC, 39% non-hospitalized did not neutralize Moreover, monoclonal antibodies (NAbs) show sharp reductions their kinetics potential P.1, but B.1.1.7. These data have implications for degree which pre-existing can protect subsequent informs policy makers susceptibility globally circulating VOC.

Language: Английский

Citations

27
Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain DOI Open Access
Denise Guerra, Laura Radić, Mitch Brinkkemper

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 9, 2024

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only few sarbecovirus strains. Therefore, there is growing interest bispecific (bsAbs) which can simultaneously target different spike epitopes thereby increase breadth prevent viral escape. Here, we generate characterize panel of 30 novel broadly reactive bsAbs using efficient controlled Fab-arm exchange protocol. We specifically combine some the broadest described far, conserved on receptor binding domain (RBD). Several show superior cross-binding neutralization compared parental sarbecoviruses from diverse clades, including recent variants. BsAbs include mAb COVA2-02 among potent broad combinations. As result, study unknown epitope that this targets distinct region at base RBD, could be when designing next-generation bsAb constructs contribute better pandemic preparedness.

Language: Английский

Citations

0
Preclinial Safety and Efficacy of a Therapeutic Antibody That Targets SARS-CoV-2 at the Sotrovimab Face But is Escaped by Omicron DOI
Jakob Kreye, S. Momsen Reincke,

Stefan Edelburg

et al.

SSRN Electronic Journal, Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 1, 2022

The recurrent emerging of novel viral variants concern (VOCs) with evasion preexisting antibody immunity upholds SARS-CoV-2 case numbers and maintain a persistent demand for updated therapies. We selected the patient-derived CV38-142 based on its potency breadth against VOCs Alpha, Beta, Gamma Delta preclinical development into therapeutic. showed in vivo efficacy Syrian hamster VOC infection model after post-exposure therapeutic application revealed favorable safety profile human protein library screen tissue cross-reactivity study. Although targets same surface as Sotrovimab which maintains activity Omicron, did not neutralize Omicron lineages BA.1 BA.2. These results highlight contingencies developing therapeutics context antigenic drift reinforce need to develop broadly neutralizing variant-proof antibodies SARS-CoV-2.Funding Information: This work was supported by German Research Foundation (DFG) (grants FOR3004, PR1274/3-1 PR1274/5- 1 H.P.; project 184695641 – SFB 958, 327654276 1315 under Germany’s Excellence Strategy Exc-2049-390688087 D.S.), Helmholtz Association (HIL-A03 H.P.), Federal Ministry Education (Connect-Generate 01GM1908D H.P) European Council (ERC) Union’s Horizon 2020 research innovation programme (Grant agreement No. 810580 D.S.).Declaration Interests: Center Neurodegenerative Diseases (DZNE) Charité-Universitätsmedizin Berlin have filed patent (application number: PCT/EP2021/064352) treatment J.K., S.M.R., H.-C.K., E.S.-S., L.E.S., V.M.C. H.P. are named inventors. is together Euroimmun GmbH recently regarding diagnostic testing. S.E., V.N., M.M., S.K., S.H., P.H. U.J. employees Miltenyi Biotec B.V. & Co. All other authors declare no competing interests.Ethics Approval Statement: animal experiment approved Landesamt für Gesundheit und Soziales Berlin, Germany (approval number 0086/20) performed compliance relevant national international guidelines care humane use animals.

Language: Английский

Citations

0