リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Design of a chimeric ACE-2/Fc-silent fusion protein with ultrahigh affinity and neutralizing capacity for SARS-CoV-2 variants」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Design of a chimeric ACE-2/Fc-silent fusion protein with ultrahigh affinity and neutralizing capacity for SARS-CoV-2 variants

Bodie, Neil M Hashimoto, Rina Connolly, David Chu, Jennifer Takayama, Kazuo Uhal, Bruce D 京都大学 DOI:10.1093/abt/tbad001

2023.01

概要

BACKGROUND: As SARS-CoV-2 continues to mutate into Variants of Concern (VOC), there is growing and urgent need to develop effective antivirals to combat COVID-19. Monoclonal antibodies developed earlier are no longer capable of effectively neutralizing currently active VOCs. This report describes the design of variant-agnostic chimeric molecules consisting of an Angiotensin-Converting Enzyme 2 (ACE-2) domain mutated to retain ultrahigh affinity binding to a wide variety of SARS-CoV-2 variants, coupled to an Fc-silent immunoglobulin domain that eliminates antibody-dependent enhancement and extends biological half-life. METHODS: Molecular modeling, Surrogate Viral Neutralization tests (sVNTs) and infection studies of human airway organoid cultures were performed with synthetic chimeras, SARS-CoV-2 spike protein mimics and SARS-CoV-2 Omicron variants B.1.1.214, BA.1, BA.2 and BA.5. RESULTS: ACE-2 mutations L27, V34 and E90 resulted in ultrahigh affinity binding of the LVE-ACE-2 domain to the widest variety of VOCs, with KDs of 93 pM and 73 pM for binding to the Alpha B1.1.7 and Omicron B.1.1.529 variants, and notably, 78fM, 133fM and 1.81pM affinities to the Omicron BA.2, BA2.75 and BQ.1.1 subvariants, respectively. sVNT assays revealed titers of ≥4.9 ng/ml, for neutralization of recombinant viral proteins corresponding to the Alpha, Delta and Omicron variants. The values above were obtained with LVE-ACE-2/mAB chimeras containing the FcRn-binding Y-T-E sequence which extends biological half-life 3-4-fold. CONCLUSIONS: The ACE-2-mutant/Fc silent fusion proteins described have ultrahigh affinity to a wide variety of SARS-CoV-2 variants including Omicron. It is proposed that these chimeric ACE-2/mABs will constitute variant-agnostic and cost-effective prophylactics against SARS-CoV-2, particularly when administered nasally.

この論文で使われている画像

関連論文

参考文献

1. Samavati, L, Uhal, B. ACE-2, much more than just a receptor for

SARS-CoV-2. Front Cell Infect Microbiol 2020; 10: 317eCollection

2020 PMID: 32582574.

2. Heurich, A, Hofmann-Winkler, H, Gierer, S et al. TMPRSS2 and

ADAM17 cleave ACE2 differentially and only proteolysis by

TMPRSS2 augments entry driven by the severe acute respiratory

syndrome coronavirus spike protein. J Virol 2014; 88: 1293–307

Epub 2013 Nov 13. PMID: 24227843; PMCID: PMC3911672.

3. Seyran, M, Takayama, K, Uversky, VN et al. The structural basis of

accelerated host cell entry by SARS-CoV-2†. FEBS J 2021; 288:

5010–20 PMID: 33264497.

4. Celik, I, Khan, A, Dwivany, FM et al. Computational prediction of

the effect of mutations in the receptor-binding domain on the

interaction between SARS-CoV-2 and human ACE2. Mol Divers

2022; 26: 3309–24 PMID: 35138508.

5. Oh, SJ, Shin, OS. SARS-CoV-2-mediated evasion strategies for

antiviral interferon pathways. J Microbiol 2022; 5: 1–10 PMID:

35122601; PMCID: PMC8817151.

6. Shah, M, Woo, HG. Omicron: a heavily mutated SARS-CoV-2

variant exhibits stronger binding to ACE2 and potently escapes

approved COVID-19 therapeutic antibodies. Front Immunol 2022;

12: 830527 PMID: 35140714; PMCID: PMC8819067.

7. Tatham, L, Sharp, J, Kijak, E et al. Lack of Ronapreve

(REGN-CoV; casirivimab and imdevimab) virological efficacy

against the SARS-CoV-2 omicron variant (B.1.1.529) in K18-hACE2

mice. bioRxiv [Preprint]. Jan 24:2022.01.23.4773972022; PMID:

35118468; PMCID: PMC8811901.

8. Planas, D, Saunders, N, Maes, P et al. Considerable escape of

SARS-CoV-2 omicron to antibody neutralization. Naturet 2022; 602:

671–75 PMID: 35016199.

9. Cameroni, E, Bowen, JE, Rosen, LE et al. Broadly neutralizing

antibodies overcome SARS-CoV-2 omicron antigenic shift. Nature

2022; 602: 664–70 PMID: 35016195.

10. Chan, KK, Dorosky, D, Sharma, P et al. Engineering human ACE2

to optimize binding to the spike protein of SARS coronavirus 2.

Science 2020; 369: 1261–5 Epub 2020 Aug 4. PMID: 32753553;

PMCID: PMC7574912.

11. Glascow, A, Glasgow, J, Limonta, D et al. Engineered ACE2

receptor traps potently neutralize SARS-CoV-2. Proc Natl Acad Sci

U S A 2020; 117: 28046–55.

12. Tanaka, S, Nelson, G, Olson, CA et al. An ACE2 triple decoy that

neutralizes SARS-CoV-2 shows enhanced affinity for virus variants.

Sci Rep 2021; 11: 12740 PMID: 34140558; PMCID: PMC8211782.

13. Maemura, T, Kuroda, M, Armbrust, T et al. Antibody-dependent

enhancement of SARS-CoV-2 infection is mediated by the IgG

receptors Fcγ RIIA and Fcγ RIIIA but does not contribute to

Downloaded from https://academic.oup.com/abt/article/6/1/59/6994056 by Kyoto University user on 15 May 2023

CONCLUSIONS

CONFLICT OF INTEREST STATEMENT

Neil Bodie DVM reports financial support was provided

by Paradigm Immunotherapeutics Inc. Bruce Uhal PhD

reports a relationship with Paradigm Immunotherapeutics Inc. that includes equity or stocks. Neil Bodie has

patent pending to Paradigm Immunotherapeutics. All other

authors have no conflicts to report.

74 Antibody Therapeutics, 2023

14.

15.

16.

17.

19.

20.

21.

22.

23.

24.

25.

26. Wilkinson, I, Anderson, S, Fry, J et al. Fc-engineered antibodies

with immune effector functions completely abolished. PLoS One

2021; 16: e0260954.

27. Dall’Acqua, WF, Woods, RM, Ward, ES et al. Increasing the

affinity of a human IgG1 for the neonatal fc receptor: biological

consequence. J Immunol 2002; 169: 5171–80.

28. Wang Q, Li Z, Ho J et al. . Resistance of SARS-CoV-2 omicron

subvariant BA.4.6 to Antibody neutralization. 2022 bioRxiv

Preprint, September 06, 2022.

29. Borrok, MJ, Mody, N, Lu, X et al. An "fc-silenced" IgG1 format

with extended half-life designed for improved stability. J Pharm Sci

2017; 106: 1008–17Epub 2017 Jan 3 PMID: 28057542.

30. Liu, P, Pan, Z, Gu, C et al. An Omalizumab biobetter antibody with

improved stability and efficacy for the treatment of allergic diseases.

Front Immunol 2020; 11: 596908 PMID: 33329588; PMCID:

PMC7728613.

31. Robbie, GJ, Criste, R, Dall’acqua, WF et al. A novel investigational

fc-modified humanized monoclonal antibody, motavizumab-YTE,

has an extended half-life in healthy adults. Antimicrob Agents

Chemother 2013; 57: 6147–53 Epub 2013 Sep 30. PMID: 24080653;

PMCID: PMC3837853.

32. Mackness, BC, Jaworski, JA, Boudanova, E et al. Antibody fc

engineering for enhanced neonatal fc receptor binding and

prolonged circulation half-life. MAbs 2019; 11: 1276–88 Epub 2019

Jul 18. PMID: 31216930; PMCID:

PMC6748615.

33. Halwe, S, Kupke, A, Vanshylla, K et al. Intranasal administration of

a monoclonal neutralizing antibody protects mice against

SARS-CoV-2 infection. Viruses 2021; 13: 1498 PMID: 34452363;

PMCID: PMC8402634.

34. Walters, BT, Jensen, PF, Larraillet, V et al. Conformational

destabilization of immunoglobulin G increases the low pH binding

affinity with the neonatal fc receptor. J Biol Chem 2016; 291:

1817–25 Epub 2015 Dec 1. PMID: 26627822; PMCID:

PMC4722460.

35. Amraei, R, Xia, C, Olejnik, J et al. Extracellular vimentin is an

attachment factor that facilitates SARS-CoV-2 entry into human

endothelial cells. Proc Natl Acad Sci U S A 2022; 119: e2113874119

PMID: 35078919.

36. Suzuki, T, Hashii, N, Tada, M et al. The influence of antibody

engineering on fc conformation and fc receptor binding properties:

analysis of FcRn-binding engineered antibodies and an fc fusion

protein. MAbs 2021; 13: 1923366 PMID: 34030575; PMCID:

PMC8158039.

Downloaded from https://academic.oup.com/abt/article/6/1/59/6994056 by Kyoto University user on 15 May 2023

18.

aberrant cytokine production by macrophages. MBio 2021; 12:

e0198721.

Sánchez-Zuno, GA, Matuz-Flores, MG, González-Estevez, G et al.

A review: antibody-dependent enhancement in COVID-19: the not

so friendly side of antibodies. Int J Immunopathol Pharmacol 2021;

35: 20587384211050199.

Junqueira, C, Crespo, Â, Ranjbar, S et al. Fcγ R-mediated

SARS-CoV-2 infection of monocytes activates inflammation. Nature

2022; 606: 576–84 PMID: 35385861.

Hou, YJ, Okuda, K, Edwards, CE et al. SARS-CoV-2 reverse

genetics reveals a variable infection gradient in the respiratory tract.

Cell 2020; 182: 429–446.e14 Epub 2020 May 27. PMID: 32526206;

PMCID: PMC7250779.

Zhang, J, Zhang, Y. A novel side-chain orientation dependent

potential derived from random-walk reference state for protein fold

selection and structure prediction. PLoS One 2010; 5: e15386 PMID:

21060880; PMCID: PMC2965178.

Zhou, H, Skolnick, J. Ab initio protein structure prediction using

chunk-TASSER. Biophys J 2007; 93: 1510–8 Epub 2007 May 11.

PMID: 17496016; PMCID: PMC1948038.

Zhou, HY, Zhou, YQ. Distance-scaled, finite ideal-gas reference

state improves structure-derived potentials of mean force for

structure selection and stability prediction. Protein Sci 2002; 11:

2714–26.

Starr, TN, Greaney, AJ, Hilton, SK et al. Deep mutational scanning

of SARS-CoV-2 receptor binding domain reveals constraints on

folding and ACE2 binding. Cell Sep 2020; 182: 1295–1310.e20Epub

2020 Aug 11 PMID: 32841599; PMCID: PMC7418704.

Tan, CW, Chia, WN, Qin, X et al. A SARS-CoV-2 surrogate virus

neutralization test based on antibody-mediated blockage of

ACE2-spike protein-protein interaction. Nat Biotechnol 2020; 38:

1073–8Epub 2020 Jul 23 PMID: 32704169.

Matsuyama, S, Nao, N, Shirato, K et al. Enhanced isolation of

SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S

A 2020; 117: 7001–3 Epub Mar 12. PMID: 32165541; PMCID:

PMC7132130.

Sano, E, Suzuki, T, Hashimoto, R et al. (2022) cell response analysis

in SARS-CoV-2 infected bronchial organoids. Commun Biol 2022; 5:

516 PMID: 35637255; PMCID: PMC9151746.

Ladel, S, Flamm, J, Zadeh, A et al. Allogenic fc domain-facilitated

uptake of IgG in nasal lamina Propria. Pharmaceutics 2018; 10: 107.

Zhu, Q, McLellan, JS, Kallewaard, NL et al. A highly potent

extended half-life antibody as a potential RSV vaccine surrogate for

all infants. Sci Transl Med 2017; 9: eaaj1928 PMID: 28469033.

...

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文

一発検索!

この論文の関連論文を見る