Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

Callaway, Heather; Hastie, Kathryn M.; Schendel, Sharon L.; Li, Haoyang; Yu, Xiaoying; Shek, Jeremy; Buck, Tierra; Hui, Sean; Bedinger, Dan; Troup, Camille; Dennison, S. Moses; Li, Kan; Alpert, Michael; Bailey, Charles C.; Benzeno, Sharon; Bonnevier, Jody; Chen, Jin‐Qiu; Chen, Charm; Cho, Hyeseon; Crompton, Peter D.; Dussupt, Vincent; Entzminger, Kevin C.; Ezzyat, Yassine; Fleming, Jonathan K.; Gilbert, Amy E.; Guan, Yongjun; Han, Xiaojian; Harvey, Christopher J.; Hatler, Julia M.; Howie, Bryan; Hu, Chao; Huang, Ailong; Imbrechts, Maya; Jin, Aishun; Kamachi, Nik; Keitany, Gladys J.; Klinger, Mark; Kolls, Jay; Krebs, Shelly J.; Li, Tingting; Luo, Feiyan; Maruyama, Toshiaki; Meehl, Michael; Mendez-Rivera, Letzibeth; Musa, Andrea; Okumura, C.J.; Rubin, Benjamin E. R.; Sato, Aaron K.; Shen, Meiying; Singh, Anirudh; Song, Shuyi; Tan, Joshua; Trimarchi, Jeffrey M.; Upadhyay, Dhruvkumar P.; Wang, Ying‐Ming; Lei, Yu; Yuan, Tom Z.; Yusko, Erik; Peters, Bjoern; Tomaras, Georgia D.; Saphire, Erica Ollmann

doi:10.1016/j.celrep.2023.112014

Cited by 14 publications

(10 citation statements)

References 19 publications

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“…The need to maintain sufficient affinity to ACE-2 probably limits SARS-CoV-2 RBD mutability as shown by the R493Q reversion mutation observed on the Omicron variants (26). Whereas antibody avidity allows to overcome SARS-CoV-2 variability(25), our data confirm that targeting multiple alternative epitopes, grants pAb to keep their binding and neutralization capacity(8). Thereby, the neutralizing activity of XAV-19, was confirmed so far on the 5 main SARS-CoV-2 variants that have emerged since the beginning of the pandemic.Limitations of the study are the following.…”

supporting

confidence: 74%

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XAV-19 a Glyco-Humanized polyclonal antibody targeting SARS-CoV-2 accelerates the recovery of mild to moderate COVID-19 patients and keeps its neutralizing activity against Omicron and its subvariants

Poulakou,

Royer,

Evgeniev

et al. 2023

Preprint

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Background: XAV-19 is a glyco-humanized swine polyclonal antibody targeting SARS-CoV-2. The safety and clinical efficacy of XAV-19 was investigated in patients with a WHO score of 2 to 4 in the WHO 7-point ordinal scale. The activity of XAV-19 against Omicron and its subvariants was assessed in vitro. Methods: A phase II/III, multicentric randomized double-blind placebo-controlled, clinical trial was conducted to evaluate the safety and clinical efficacy of XAV-19 in inpatients with COVID-19 requiring or not oxygen therapy and outpatients not requiring oxygen (EUROXAV trial,NCT04928430). Most patients were not vaccinated. The primary endpoint was the proportion of patients with an aggravation of COVID-19 within 8 days after treatment. Binding and neutralization of Omicron or its subvariants by XAV-19 was investigated by ELISA or with a whole virus neutralization assay. Results: Patients received either 150mg of XAV-19 (N=139) or placebo (N=140). Low enrolment forced the premature trial termination. XAV-19 was well tolerated. No difference in the primary endpoint, nor in the proportion with an improvement at day 8 (secondary endpoint) was observed between the 2 groups. For patients not requiring oxygen therapy, XAV-19 reduced the time to improvement significantly (7 days vs 14 days p=0.0159). Neutralizing activity against Omicron and BA.2, BA2.12.1, BA.4/5 and BQ1.1 subvariants was shown in vitro. Conclusions: XAV-19 did not reduce the aggravation in COVID-19 patients. While it did not bring any benefit to patients requiring oxygen, it reduced the time to improvement for patients not requiring oxygen (WHO score 2 or 3). These preliminary clinical data might indicate a therapeutic potential for patients with mild to moderate COVID-19 requiring supplementation with anti-SARS-CoV-2 neutralizing antibodies.

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supporting

confidence: 74%

“…Due to its high number of mutations (30 mutations in the spike protein, 15 in the RBD), Omicron showed resistance to more than 80% of the therapeutic antibody candidate (25). Yet these mutations represent only 3% of the main target epitopes of XAV-19.…”

Section: Discussionmentioning

confidence: 99%

XAV-19 a Glyco-Humanized polyclonal antibody targeting SARS-CoV-2 accelerates the recovery of mild to moderate COVID-19 patients and keeps its neutralizing activity against Omicron and its subvariants

Poulakou,

Royer,

Evgeniev

et al. 2023

Preprint

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“…b , Pre-selected CDR pools were amplified from phage and combined by overlap PCR to create separate combined light and combined heavy chain libraries. The light chain library was further selected on the Beta variant, resulting in the engineered clone LxC1-G10, which showed potent neutralization of BA.1 and was thoroughly characterized by the Coronavirus Immunotherapy Consortium (CoVIC) at La Jolla Institute of Immunology 29 . The heavy chain library was selected on a combination of Alpha, Beta, Gamma, and Epsilon variants to broaden neutralization activity.…”

Section: Resultsmentioning

confidence: 99%

“…Both our early lead candidate hN2Y (COVIC-359) and LxC1-G10 (COVIC-362) were submitted to the Coronavirus Immunotherapy Consortium (CoVIC) at La Jolla Institute of Immunology for analysis and testing against over 350 other therapeutic antibody candidates 28,29 . Both antibodies showed nearly 100% protection against cell infection in pseudovirus neutralization assay for Beta, Delta, BA.1, BA.1.1, and BA.2 variants, and showed efficacy with live Wuhan-Hu-1 virus in both neutralization assay and during in vivo mouse challenge.…”

Section: Discussionmentioning

confidence: 99%

Rapid engineering of SARS-CoV-2 therapeutic antibodies to increase breadth of neutralization including XBB.1.5 and BQ.1.1

Entzminger¹,

Fleming²,

Entzminger³

et al. 2023

Preprint

Self Cite

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An antibody panel that broadly neutralizes currently circulating Omicron variants was obtained byin vitroaffinity maturation using phage display. Starting from a single parent clone, antibody engineering was performed in iterative stages in real time as variants emerged using a proprietary technology called STage-Enhanced Maturation (STEM). Humanized from a rabbit antibody, the parent clone showed undetectable neutralization of later Omicron variants, while an early stage IgG possessing only an engineered light chain potently neutralizes some BA.2 but not BA.4/BA.5 lineage variants. However, the final heavy and light chain engineered mAbs show potent neutralization of XBB.1.5 and BQ.1.1 by surrogate virus neutralization test, and biolayer interferometry shows pM KDaffinity for both variants. Our work not only details novel therapeutic candidates but also validates a unique general strategy to create broadly neutralizing mAbs to current and future SARS-CoV-2 variants.

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“…Thus, in a humoral immune response dominated by IgM, intra-and inter-spike binding may become paramount for efficient neutralisation and retaining activity against escape variants as described for bivalent IgG against SARS-CoV-2 and other viruses [52][53][54]. Concerning the NTD supersite, Fab fragments derived from potently neutralising antibodies have been reported to lose their neutralising activity [55].…”

Section: Discussionmentioning

confidence: 99%

Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection

Günther,

Schöfbänker,

Lorentzen

et al. 2024

Preprint

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Neutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the intra-host evolution and the humoral immune response in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81.Bamlanivimab treatment early in infection was associated with the emergence of the bamlanivimab escape mutation S:S494P. Ten days before virus elimination, additional mutations within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S were observed, of which the triple mutant S:Delta141-4 E484K S494P became dominant. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test (pVNT), surrogate VNT (sVNT), and immunoglobulin-capture EIA showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in a massive increase of Omicron-reactive antibodies.In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the emergence of escape variants with known epidemiological relevance.

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Bivalent intra-spike binding provides durability against emergent Omicron lineages: Results from a global consortium

Cited by 14 publications

References 19 publications

XAV-19 a Glyco-Humanized polyclonal antibody targeting SARS-CoV-2 accelerates the recovery of mild to moderate COVID-19 patients and keeps its neutralizing activity against Omicron and its subvariants

XAV-19 a Glyco-Humanized polyclonal antibody targeting SARS-CoV-2 accelerates the recovery of mild to moderate COVID-19 patients and keeps its neutralizing activity against Omicron and its subvariants

Rapid engineering of SARS-CoV-2 therapeutic antibodies to increase breadth of neutralization including XBB.1.5 and BQ.1.1

Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection

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