Bamlanivimab + etesevimab therapy induces SARS-CoV-2 immune escape mutations and secondary clinical deterioration in COVID-19 patients with B-cell malignancies

Pommeret, Fanny; Colomba, Johann; Bigenwald, Camille; Laparra, Ariane; Bockel, S.; Bayle, Arnaud; Michot, Jean‐Marie; Hueso, Thomas; Albigès, Laurence; Tiberghien, Pierre; Marot, Stéphane; Jary, Aude; Lacombe, Karine; Barlési, Fabrice; Griscelli, Frank; Colomba, Emeline

doi:10.1016/j.annonc.2021.07.015

Cited by 38 publications

(28 citation statements)

References 6 publications

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“…The Alpha variant is refractory to neutralization by most mAbs, which target the NTD of Spike protein and also resistant to several RBD-specific mAbs (9). Mutations in the Beta lineage (K417N, E484K, and N501Y in RBD), especially mutations of Spike at E484 but also in the Nterminal domain (NTD; L18F, D80A, D215G, D242-244, and R246I in SA variant (10,11)), reduce neutralization sensitivity or confer neutralization escape from multiple mAbs (4,5,(12)(13)(14)(15)(16)(17)(18)(19)(20). Third, polyclonal antibodies produced in their Fab'2 format from horses (21) or in their IgG format from humanized cows (22) or glyco-humanized pigs (23) have also proven efficacy to neutralize SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Vanhove¹,

Marot

et al. 2021

Front. Immunol.

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Amino acid substitutions and deletions in the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can reduce the effectiveness of monoclonal antibodies (mAbs). In contrast, heterologous polyclonal antibodies raised against S protein, through the recognition of multiple target epitopes, have the potential to maintain neutralization capacities. XAV-19 is a swine glyco-humanized polyclonal neutralizing antibody raised against the receptor binding domain (RBD) of the Wuhan-Hu-1 Spike protein of SARS-CoV-2. XAV-19 target epitopes were found distributed all over the RBD and particularly cover the receptor binding motives (RBMs), in direct contact sites with the angiotensin converting enzyme-2 (ACE-2). Therefore, in Spike/ACE-2 interaction assays, XAV-19 showed potent neutralization capacities of the original Wuhan Spike and of the United Kingdom (Alpha/B.1.1.7) and South African (Beta/B.1.351) variants. These results were confirmed by cytopathogenic assays using Vero E6 and live virus variants including the Brazil (Gamma/P.1) and the Indian (Delta/B.1.617.2) variants. In a selective pressure study on Vero E6 cells conducted over 1 month, no mutation was associated with the addition of increasing doses of XAV-19. The potential to reduce viral load in lungs was confirmed in a human ACE-2 transduced mouse model. XAV-19 is currently evaluated in patients hospitalized for COVID-19-induced moderate pneumonia in phase 2a-2b (NCT04453384) where safety was already demonstrated and in an ongoing 2/3 trial (NCT04928430) to evaluate the efficacy and safety of XAV-19 in patients with moderate-to-severe COVID-19. Owing to its polyclonal nature and its glyco-humanization, XAV-19 may provide a novel safe and effective therapeutic tool to mitigate the severity of coronavirus disease 2019 (COVID-19) including the different variants of concern identified so far.

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Section: Introductionmentioning

confidence: 99%

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Vanhove¹,

Marot

et al. 2021

Front. Immunol.

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“…Although the BLAZE-1 trial showed that both monotherapy with bamlanivimab and combination therapy with bamlanivimab and etesevimab reduced the risk of hospitalization and COVID-19 progression compared to a placebo group [8], some concerns remain over the risk of mutation emergence in the S gene under selective pressure from monotherapy with bamlanivimab [9]. Some cases of Q493R mutations following bamlanivimab/etesevimab administration were also reported in the literature and are associated with a reduced viral clearance and, in some patients, with fatal outcome [10][11][12][13].…”

Section: Introductionmentioning

confidence: 95%

Spike Gene Evolution and Immune Escape Mutations in Patients with Mild or Moderate Forms of COVID-19 and Treated with Monoclonal Antibodies Therapies

Jary

Marot

Fayçal

et al. 2022

Viruses

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We explored the molecular evolution of the spike gene after the administration of anti-spike monoclonal antibodies in patients with mild or moderate forms of COVID-19. Four out of the 13 patients acquired a mutation during follow-up; two mutations (G1204E and E406G) appeared as a mixture without clinical impact, while the Q493R mutation emerged in two patients (one receiving bamlanivimab and one receiving bamlanivimab/etesevimab) with fatal outcomes. Careful virological monitoring of patients treated with mAbs should be performed, especially in immunosuppressed patients.

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“…in low and middle income countries) 4 , scarce, or ineffective (i.e. in the context of mAb-resistant variants) 5 . COVID-19 convalescent plasma (CCP) is safe in hospitalized populations 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

Sullivan

Gebo

Shoham

et al. 2021

Preprint

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BACKGROUND: The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain. METHODS: This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults >18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021. RESULTS: A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions. CONCLUSION: Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic.

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Bamlanivimab + etesevimab therapy induces SARS-CoV-2 immune escape mutations and secondary clinical deterioration in COVID-19 patients with B-cell malignancies

Abstract: Bamlivimab + etesevimab therapy induces SARS-COV-2 immune escape mutations and secondary clinical deterioration in Covid-19 patients with B cell malignancies F.

Cited by 38 publications

References 6 publications

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

XAV-19, a Swine Glyco-Humanized Polyclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Domain, Targets Multiple Epitopes and Broadly Neutralizes Variants

Spike Gene Evolution and Immune Escape Mutations in Patients with Mild or Moderate Forms of COVID-19 and Treated with Monoclonal Antibodies Therapies

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma

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