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RESEARCH ARTICLE (Open Access)

Acute treatment with monoclonal antibodies: their design and their use

Anthony D Kelleher
+ Author Affiliations
- Author Affiliations

The Kirby Institute, UNSW Sydney, NSW, Australia. Email: akelleher@kirby.unsw.edu.au

Microbiology Australia 42(1) 39-43 https://doi.org/10.1071/MA21011
Submitted: 1 February 2021  Accepted: 18 February 2021   Published: 9 April 2021

Journal Compilation © The Authors 2021 Open Access CC BY, published (by CSIRO Publishing) on behalf of the ASM

Abstract

Passive anti-viral immunotherapy, including monoclonal antibodies (mAb), was identified early as a promising therapeutic avenue for COVID-19 with a rapid development pathway. This has been driven by the lack of existing effective direct acting antivirals for coronaviruses, the marginal clinical impact of remdesivir and the relative lack of efficacy of antivirals against other respiratory pathogens, combined with the failure of repurposed drugs. This review explores the potential utility of mAb targeting SARS-CoV-2, to prevent or treat COVID-19 infection. The use of mAb against host factors (e.g. tocilizumab targeting IL-6 receptor and canakinumab targeting IL1-β) to mitigate the inflammatory response seen in progressive disease will not be considered. This review will primarily consider mAb that have direct neutralising activity via their targeting of the SARS-CoV-2 Spike (S) protein focussing on: the targets of mAb; how they mediate viral neutralisation; their propensity to generate escape mutants; their clinical use so far, and their likely place in the therapeutic play book.


References

[1]  Man, W.H. et al. (2020) Infant respiratory syncytial virus prophylaxis and nasopharyngeal microbiota until 6 years of life: a subanalysis of the MAKI randomised controlled trial. Lancet Respir. Med. 8, 1022–1031.
Infant respiratory syncytial virus prophylaxis and nasopharyngeal microbiota until 6 years of life: a subanalysis of the MAKI randomised controlled trial.Crossref | GoogleScholarGoogle Scholar | 32203712PubMed |

[2]  Blanken, M.O. et al. (2018) Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants. Eur. J. Pediatr. 177, 133–144.
Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants.Crossref | GoogleScholarGoogle Scholar | 29168012PubMed |

[3]  Mulangu, S. et al. (2019) A randomized, controlled trial of Ebola virus disease therapeutics. N. Engl. J. Med. 381, 2293–2303.
A randomized, controlled trial of Ebola virus disease therapeutics.Crossref | GoogleScholarGoogle Scholar | 31774950PubMed |

[4]  Ishida, J.H. et al. (2017) Phase 2 randomized, double-blind, placebo-controlled trial of RG7667, a combination monoclonal antibody, for prevention of cytomegalovirus infection in high-risk kidney transplant recipients. Antimicrob. Agents Chemother. 61, e01794-16.
Phase 2 randomized, double-blind, placebo-controlled trial of RG7667, a combination monoclonal antibody, for prevention of cytomegalovirus infection in high-risk kidney transplant recipients.Crossref | GoogleScholarGoogle Scholar | 27872061PubMed |

[5]  Wilcox, M.H. et al. (2017) Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N. Engl. J. Med. 376, 305–317.
Bezlotoxumab for prevention of recurrent Clostridium difficile infection.Crossref | GoogleScholarGoogle Scholar | 28121498PubMed |

[6]  Cohen, Y.Z. et al. (2019) Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: a randomized, phase 1 study. PLoS One 14, e0219142.
Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: a randomized, phase 1 study.Crossref | GoogleScholarGoogle Scholar | 31393868PubMed |

[7]  Crowell, T.A. et al. (2019) Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet HIV 6, e297–e306.
Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial.Crossref | GoogleScholarGoogle Scholar | 31000477PubMed |

[8]  Walls, A.C. et al. (2020) Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 183, 1735.
Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein.Crossref | GoogleScholarGoogle Scholar | 33306958PubMed |

[9]  Wrapp, D. et al. (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263.
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Crossref | GoogleScholarGoogle Scholar | 32075877PubMed |

[10]  Cai, Y. et al. (2020) Distinct conformational states of SARS-CoV-2 spike protein. Science 369, 1586–1592.
| 32694201PubMed |

[11]  Hoffmann, M. et al. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280 e8.
SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Crossref | GoogleScholarGoogle Scholar | 32142651PubMed |

[12]  Cantuti-Castelvetri, L. et al. (2020) Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370, 856–860.
Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.Crossref | GoogleScholarGoogle Scholar | 33082293PubMed |

[13]  Li, W. et al. (2003) Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450–454.
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Crossref | GoogleScholarGoogle Scholar | 14647384PubMed |

[14]  Wang, N. et al. (2013) Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res. 23, 986–993.
Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4.Crossref | GoogleScholarGoogle Scholar | 23835475PubMed |

[15]  Wang, Q. et al. (2020) Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904.e9.
Structural and functional basis of SARS-CoV-2 entry by using human ACE2.Crossref | GoogleScholarGoogle Scholar | 32275855PubMed |

[16]  Tea, F. et al. (2021) SARS-CoV-2 neutralizing antibodies; longevity, breadth, and evasion by emerging viral variants. medRxiv. , .
SARS-CoV-2 neutralizing antibodies; longevity, breadth, and evasion by emerging viral variants.Crossref | GoogleScholarGoogle Scholar |

[17]  Rodda, L.B. et al. (2021) Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell 184, 169–183.e17.
Functional SARS-CoV-2-specific immune memory persists after mild COVID-19.Crossref | GoogleScholarGoogle Scholar | 33296701PubMed |

[18]  Finkelstein, M.T. et al. (2021) Structural analysis of neutralizing epitopes of the SARS-CoV-2 spike to guide therapy and vaccine design strategies. Viruses 13, 134.
Structural analysis of neutralizing epitopes of the SARS-CoV-2 spike to guide therapy and vaccine design strategies.Crossref | GoogleScholarGoogle Scholar | 33477902PubMed |

[19]  Jackson, L.A. et al. (2020) An mRNA vaccine against SARS-CoV-2: preliminary report. N. Engl. J. Med. 383, 1920–1931.
An mRNA vaccine against SARS-CoV-2: preliminary report.Crossref | GoogleScholarGoogle Scholar | 32663912PubMed |

[20]  Folegatti, P.M. et al. (2020) Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478.
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.Crossref | GoogleScholarGoogle Scholar | 32702298PubMed |

[21]  Zhu, F.C. et al. (2020) Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 396, 479–488.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.Crossref | GoogleScholarGoogle Scholar | 32702299PubMed |

[22]  Walsh, E.E. et al. (2020) Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450.
Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates.Crossref | GoogleScholarGoogle Scholar | 33053279PubMed |

[23]  Barnes, C.O. et al. (2020) SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature 588, 682–687.
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.Crossref | GoogleScholarGoogle Scholar | 33045718PubMed |

[24]  Hansen, J. et al. (2020) Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 369, 1010–1014.
Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.Crossref | GoogleScholarGoogle Scholar | 32540901PubMed |

[25]  Huo, J. et al. (2020) Neutralization of SARS-CoV-2 by destruction of the prefusion spike. Cell Host Microbe 28, 497.
Neutralization of SARS-CoV-2 by destruction of the prefusion spike.Crossref | GoogleScholarGoogle Scholar | 32910920PubMed |

[26]  Liu, L. et al. (2020) Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 584, 450–456.
Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike.Crossref | GoogleScholarGoogle Scholar | 32698192PubMed |

[27]  Yuan, M. et al. (2020) A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630–633.
A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV.Crossref | GoogleScholarGoogle Scholar | 32245784PubMed |

[28]  McCallum  M.et al2021 N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2.bioRxiv.

[29]  Wang, N. et al. (2019) Structural definition of a neutralization-sensitive epitope on the MERS-CoV S1-NTD. Cell Rep. 28, 3395–3405 e6.
Structural definition of a neutralization-sensitive epitope on the MERS-CoV S1-NTD.Crossref | GoogleScholarGoogle Scholar | 31553909PubMed |

[30]  Kemp  S.A.et al. (2020 ) Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.medRxiv.

[31]  ACTIV-3/TICO LY-CoV555 Study Group et al. (2020) A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N. Engl. J. Med. , .
| 33394576PubMed |

[32]  Chen, P. et al. (2021) SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N. Engl. J. Med. 384, 229–237.
SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19.Crossref | GoogleScholarGoogle Scholar | 33113295PubMed |

[33]  Weinreich, D.M. et al. (2021) REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N. Engl. J. Med. 384, 238–251.
REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19.Crossref | GoogleScholarGoogle Scholar | 33332778PubMed |

[34]  Wang, S.F. et al. (2014) Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins. Biochem. Biophys. Res. Commun. 451, 208–214.
Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins.Crossref | GoogleScholarGoogle Scholar | 25073113PubMed |