Protective Non-neutralizing anti–N-terminal Domain mAb Maintains Fc-mediated Function against SARS-COV-2 Variants up to BA.2.86-JN.1 with Superfluous In Vivo Protection against JN.1 Due to Attenuated Virulence DOI

Arman Izadi,

Magdalena Godzwon, Anna Söderlund‐Strand

и другие.

The Journal of Immunology, Год журнала: 2024, Номер 213(5), С. 678 - 689

Опубликована: Июль 17, 2024

Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal (NTD), Ab81 Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these maintain function Ag binding mutated variants. Ab94 retained their nanomolar affinity toward Omicron its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, BQ1.1. However, when encountering more heavily BA.2.86, lost function, whereas 10 new mutations NTD did not affect Ab94. vivo experiments with mice inoculated a stringent dose 100,000 PFU JN.1 variant revealed unexpected results. Surprisingly, exhibited low disease manifestation animal model no weight loss or death control group. Still, assessment using clinical scoring system showed better protection for Ab94-treated mice, indicating still beneficial. Our work shows anti-receptor-binding mAb reactivity BA.2.86 emerged, anti-NTD was functional. Finally, adds insight into evolution virus by reporting is substantially less virulent than previous strains.

Язык: Английский

Protective non-neutralizing SARS-CoV-2 monoclonal antibodies DOI Creative Commons

Arman Izadi,

Pontus Nordenfelt

Trends in Immunology, Год журнала: 2024, Номер 45(8), С. 609 - 624

Опубликована: Июль 20, 2024

Recent studies show an important role for non-neutralizing anti-spike antibodies, including monoclonal antibodies (mAbs), in robustly protecting against SARS-CoV-2 infection. These mAbs use Fc-mediated functions such as complement activation, phagocytosis, and cellular cytotoxicity. There is untapped potential using durable antibody treatments; because of their available conserved epitopes, they may not be sensitive to virus mutations neutralizing mAbs. Here, we discuss evidence mAb-mediated protection We explore how mAb can enhanced via novel antibody-engineering techniques. Important questions remain answered regarding the characteristics protective mAbs, models assays used study, risks ensuing detrimental inflammation, well durability mechanisms protection.

Язык: Английский

Процитировано

8
A Structural Voyage Toward the Landscape of Humoral and Cellular Immune Escapes of SARS‐CoV‐2 DOI Open Access

Jun Liu,

Yan Wu, George F. Gao

и другие.

Immunological Reviews, Год журнала: 2025, Номер 330(1)

Опубликована: Фев. 5, 2025

ABSTRACT The genome‐based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in the past nearly 5 years since its emergence has refreshed our understanding virus evolution, especially on convergent co‐evolution with host. SARS‐CoV‐2 evolution been characterized by sets mutations that affect functional properties altering infectivity, virulence, transmissibility, and interactions host immunity. This poses a huge challenge to global prevention control measures based drug treatment vaccine application. As one key evasion strategies response immune profile human population, there are overwhelming amounts evidence for reduced antibody neutralization variants. Additionally, data also suggest levels CD4 + CD8 T‐cell responses against variants or sub‐variants decrease populations, although non‐negligible cross‐T‐cell maintained. Herein, from perspectives structural immunology, we outline characteristics mechanisms T cell SARS‐CoV variants/sub‐variants. molecular bases impact escaping interaction epitopes receptors adaptive immunity, is, major histocompatibility complex (MHC), receptor (TCR), summarized discussed, knowledge which will widen this pandemic‐threatening assist preparedness Pathogen X future.

Язык: Английский

Процитировано

0
Dissecting the properties of circulating IgG against streptococcal pathogens through a combined systems antigenomics-serology workflow DOI Creative Commons
Alejandro Gómez Toledo,

Sounak Chowdhury,

Elisabeth Hjortswang

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 24, 2025

Abstract This study showcases an integrative mass spectrometry-based strategy combining systems antigenomics and serology to characterize human antibodies in clinical samples. involves using circulating plasma affinity-enrich antigenic proteins biochemically fractionated pools of bacterial proteins, followed by their identification quantification spectrometry. A selected subset the identified antigens is then expressed recombinantly isolate antigen-specific IgG, characterization structural functional properties these antibodies. We focused on Group streptococcus (GAS), a major pathogen lacking approved vaccine. The data shows that both healthy GAS-infected individuals have IgG against conserved streptococcal including toxins virulence factors. breadth remains relatively constant across but changes considerably GAS bacteremia. Moreover, analysis reveals individual variation titers, subclass distributions, Fc-signaling capacity, despite similar epitope Fc-glycosylation patterns. Finally, we show may cross-react with Streptococcus dysgalactiae (SD), occupies niches causes comparable infections. Collectively, our results highlight complexity GAS-specific antibody responses versatility methodology immune pathogens.

Язык: Английский

Процитировано

0
Enhancing complement activation by therapeutic anti-tumor antibodies: Mechanisms, strategies, and engineering approaches DOI Creative Commons
Vitalijs Ovcinnikovs, Karin Dijkman, Gijs G. Zom

и другие.

Seminars in Immunology, Год журнала: 2024, Номер 77, С. 101922 - 101922

Опубликована: Дек. 31, 2024

Язык: Английский

Процитировано

2
Stellabody: A novel hexamer‐promoting mutation for improved IgG potency DOI Creative Commons
Clarissa A. Whitehead, Bruce D. Wines, Anna M. Davies

и другие.

Immunological Reviews, Год журнала: 2024, Номер unknown

Опубликована: Окт. 4, 2024

Summary Advances in antibody engineering are being directed at the development of next generation immunotherapeutics with improved potency. Hexamerisation IgG is a normal physiological aspect biology and recently described mutations that facilitate this process have substantial impact upon monoclonal behavior resulting elicitation dramatically enhanced complement‐dependent cytotoxicity, Fc receptor function, antigen binding effects, such as targeted agonism or microbe neutralization. Whereas discovery hexamerisation enhancing has largely focused on residues exposure surface Fc‐Fc CH2‐CH3 interfaces, our unique approach mostly buried residue H429 CH3 domain. Selective substitution position 429 forms basis Stellabody technology, where choice amino acid results distinct outcomes. H429F monomeric hexamerises after target binding, so called “on‐target” hexamerisation, while H429Y mutant pH‐sensitive hexamers in‐solution prior to binding. Moreover, technologies broadly applicable across family antibody‐based biologic therapeutics, including conventional mAbs, bispecific Ig‐like biologics Fc‐fusions, applications diverse diseases.

Язык: Английский

Процитировано

1
Protective Non-neutralizing anti–N-terminal Domain mAb Maintains Fc-mediated Function against SARS-COV-2 Variants up to BA.2.86-JN.1 with Superfluous In Vivo Protection against JN.1 Due to Attenuated Virulence DOI

Arman Izadi,

Magdalena Godzwon, Anna Söderlund‐Strand

и другие.

The Journal of Immunology, Год журнала: 2024, Номер 213(5), С. 678 - 689

Опубликована: Июль 17, 2024

Substantial evidence supports that Fc-mediated effector functions of anti-spike Abs contribute to anti-SARS-Cov-2 protection. We have previously shown two non-neutralizing but opsonic mAbs targeting the receptor-binding domain and N-terminal (NTD), Ab81 Ab94, respectively, are protective against lethal Wuhan SARS-CoV-2 infection in K18-hACE2 mice. In this article, we investigated whether these maintain function Ag binding mutated variants. Ab94 retained their nanomolar affinity toward Omicron its subvariants, such as BA.2, BA.4, BA.5, XBB, XBB1.5, BQ1.1. However, when encountering more heavily BA.2.86, lost function, whereas 10 new mutations NTD did not affect Ab94. vivo experiments with mice inoculated a stringent dose 100,000 PFU JN.1 variant revealed unexpected results. Surprisingly, exhibited low disease manifestation animal model no weight loss or death control group. Still, assessment using clinical scoring system showed better protection for Ab94-treated mice, indicating still beneficial. Our work shows anti-receptor-binding mAb reactivity BA.2.86 emerged, anti-NTD was functional. Finally, adds insight into evolution virus by reporting is substantially less virulent than previous strains.

Язык: Английский

Процитировано

0