Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

AbstractHeterophilic antibodies are still an important source of interference in immunoassays. We have conducted a screening study for interference in a panel of commercially available assays using two sera known to contain high titer Fc-reactive heterophilic antibodies.The sera were distributed to laboratories participating in the Nordic External Quality Assessment cooperation (EQANord). Duplicate samples pre-blocked with aggregated murine monoclonal MAK33 were also supplied. Discrepancies (>50%) between the results for native and blocked samples were used to classify the tested assays as susceptible to interference. A total of 170 different assay kits covering 91 analytes were tested.We found that 21 assays, covering 19 different analytes, were susceptible to interference from the heterophilic antibodies in the two sera. Many of these are clinically and commercially important assays. Some of the false results were grossly elevated and could have been detrimental to patient care in a clinical setting.Heterophilic antibodies with Fc-reactivity remain a threat. A more widespread use of antibody fragments and aggregated immunoglobulin could potentially improve the heterophilic antibody resistance of assays intended for clinical use.

Download Full-text

Emergence of Fc-Gamma-Riib-Dominance Contributes to Resistance to Therapeutic Antibodies in Patients with Chronic Lymphocytic Leukaemia

Blood ◽

10.1182/blood.v126.23.447.447 ◽

2015 ◽

Vol 126 (23) ◽

pp. 447-447

Author(s):

Melinda Burgess ◽

Sally Mapp ◽

Roberta Mazzieri ◽

Jonathan Ellis ◽

Catherine Cheung ◽

...

Keyword(s):

Chronic Lymphocytic Leukaemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Primary Cultures ◽

Differential Sensitivity ◽

Moderate Activity ◽

Therapeutic Antibodies ◽

Advisory Committees ◽

Antibody Resistance

Abstract Aim: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Whilst therapeutic antibodies show clinical activity in CLL patients, resistance develops. Thus, identifying mechanisms of antibody resistance and methods to reduce resistance would be valuable in managing CLL. Results: In this study we show that a therapeutic antibody against CD62L is able to induce antibody-dependent cell mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. Significantly, we observed that patients with stable disease retained sensitivity to CD62L-Ab whilst untreated patients, whose disease progressed, became progressively resistant to CD62L-Ab. Using strategies to enrich for monocytes we were able to show that the CD62L-Ab dependent killing was attributable to an FcγR-dependent mechanism within the monocyte derived cell (MDC) fraction of PBMCs. Transcriptomic profiling and marker analysis indicated that the MDCs acquired a macrophage phenotype. Both MDCs from antibody-sensitive or antibody-resistant patients were able to bind Ab-bound CLL cells equally. Moreover, resistance could not be attributed to reduced numbers of monocytes or macrophages or to distinct subtypes of monocytes or macrophages. Using pharmacological inhibitors of the activating pathway of FcγR signaling and the inhibitory FcγRIIB pathway we were able to show that the antibody resistance in MDCs, derived from patients with CLL, was due to the emerging dominance of the FcγRIIb pathway relative to the activating FcγR pathways. We examined whether the differential sensitivity to CD62L-Ab was also evident for anti-CD20 antibodies used clinically for CLL. Rituximab showed only moderate activity in vitro and no clear difference in cytotoxicity was observed between patients who were previously identified as being resistant or sensitive to the CD62L antibody. Obinutuzumab invoked similar differential cell killing in PBMCs from patients sensitive to, or resistant to, CD62L-Ab. Further comparison indicated that CD62L-Ab and obinutuzumab induced similar malignant B cell binding to MDCs and ADP in contrast to rituximab. Finally, similar to anti-CD62L, ADCC/ADP response to obinutuzumab was reduced following treatment of sensitive cultures with a syk or BTK inhibitor and increased in MDCs derived from resistant patients treated with a Ship1 inhibitor. Conclusions: These data establish, for the first time, that MDCs derived from CLL patients may switch from an antibody sensitive phenotype to an antibody-resistant phenotype as disease progresses. Significantly, we show that the resistance to MDC-mediated ADCC/ADP may be reversed by the inhibition of FcγRIIB with pharmacological modifiers. Disclosures Mollee: Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding.

Download Full-text

Addition of the Akt inhibitor triciribine overcomes antibody resistance in cells from ErbB2/Neu-positive/PTEN-deficient mammary tumors

International Journal of Oncology ◽

10.3892/ijo.2014.2271 ◽

2014 ◽

Vol 44 (4) ◽

pp. 1277-1283 ◽

Cited By ~ 7

Author(s):

QINGFEI WANG ◽

HUI DING ◽

BAORUI LIU ◽

SHAU-HSUAN LI ◽

PING LI ◽

...

Keyword(s):

Mammary Tumors ◽

Akt Inhibitor ◽

Antibody Resistance ◽

In Cells

Download Full-text

Accurate Prediction of Antibody Resistance in Clinical HIV-1 Isolates

10.1101/364828 ◽

2018 ◽

Cited By ~ 1

Author(s):

Reda Rawi ◽

Raghvendra Mall ◽

Chen-Hsiang Shen ◽

Nicole A. Doria-Rose ◽

S. Katie Farney ◽

...

Keyword(s):

Machine Learning ◽

Clinical Trials ◽

Neutralizing Antibodies ◽

Gradient Boosting ◽

Clinical Settings ◽

Gradient Boosting Machine ◽

Resistant Strains ◽

Antibody Resistance ◽

Hiv 1

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have promising utility in prevention and treatment of HIV-1 infection with several undergoing clinical trials. Due to high sequence diversity and mutation rate of HIV-1, viral isolates are often resistant to particular bNAbs. Resistant strains are commonly identified by time-consuming and expensive in vitro neutralization experiments. Here, we developed machine learning-based classifiers that accurately predict resistance of HIV-1 strains to 33 neutralizing antibodies. Notably, our classifiers achieved an overall prediction accuracy of 96% for 212 clinical isolates from patients enrolled in four different clinical trials. Moreover, use of the tree-based machine learning method gradient boosting machine enabled us to identify critical epitope features that distinguish between antibody resistance and sensitivity. The availability of an in silico antibody resistance predictor will facilitate informed decisions of antibody usage in clinical settings.

Download Full-text

Panitumumab and cetuximab affect differently miRNA expression in colorectal cancer cells

Biomarkers in Medicine ◽

10.2217/bmm-2020-0520 ◽

2021 ◽

Author(s):

Romain Chautard ◽

Laetitia Corset ◽

Sajida Ibrahim ◽

Céline Desvignes ◽

Gilles Paintaud ◽

...

Keyword(s):

Colorectal Cancer ◽

Monoclonal Antibody ◽

Monoclonal Antibodies ◽

Cancer Cells ◽

Two Phase ◽

Colorectal Cancer Cells ◽

Significant Expression ◽

Antibody Resistance ◽

Phase Process

Structured abstract Background & aim: Resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC) is frequent and prognostic biomarkers are lacking. MicroRNAs (miR) are good candidates in this context. We aimed to characterize cetuximab and panitumumab exposure influence on miR expression in colorectal cancer cells to identify those regulating the EGFR pathway and implicated in resistance to treatment. Finally, we aimed to identify miR expression in serum of patients with advanced CRC treated with cetuximab or panitumumab. Results: Cetuximab and panitumumab exposure induced significant expression variations of 17 miR out of a miRnome panel of 752. Six of those miR interacted with at least one downstream element of the EGFR pathway. Conclusion: After the bioinformatics two-phase process, 5 miR rarely described before could be potential actors of anti-EGFR monoclonal antibody resistance: miR-95-3p, miR-139-5p, miR-145-5p, miR-429 and miR-1247-5p. In vivo, we detected the expression of miR-139-5p and miR-145-5p in serum of patients with metastatic CRC.

Download Full-text

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

10.26434/chemrxiv.14645217.v1 ◽

2021 ◽

Author(s):

Son Tung Ngo

Keyword(s):

Structural Change ◽

Antibody Fragment ◽

Neutralizing Antibody ◽

Md Simulations ◽

Atomic Scale ◽

Atomistic Simulations ◽

S Protein ◽

Mutation System ◽

Biological Target ◽

Antibody Resistance

<div> <p><a>SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. </a>However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, backbone RMSD of the 501Y.V2 complex was significantly larger than that of the WT implying a large structural change of the mutation system. Moreover, the mean of , CCS, and SASA are almost the same when compared two complexes, but the distribution of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).</p> </div>

Download Full-text

SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion

10.1101/2021.06.17.448820 ◽

2021 ◽

Author(s):

Akatsuki Saito ◽

Hesham Nasser ◽

Keiya Uriu ◽

Yusuke Kosugi ◽

Takashi Irie ◽

...

Keyword(s):

Cell Fusion ◽

Viral Genome ◽

Neutralizing Antibody ◽

Spike Protein ◽

Human Society ◽

Viral Infectivity ◽

Viral Fusion ◽

Antibody Resistance ◽

Cell Cell

During the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and at least five variants of concerns (VOCs) have been considered as the hazardous SARS-CoV-2 variants to the human society. The newly emerging VOC, the B.1.617.2 lineage (delta variant), closely associates with a huge COVID-19 surge in India in Spring 2021. However, its virological property remains unclear. Here, we show that the B.1.617 variants are highly fusogenic and form prominent syncytia. Bioinformatic analyses reveal that the P681R mutation in the spike protein is highly conserved in this lineage. Although the P681R mutation decreases viral infectivity, this mutation confers the neutralizing antibody resistance. Notably, we demonstrate that the P681R mutation facilitates the furin-mediated spike cleavage and enhances and accelerates cell-cell fusion. Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest VOC, which may associate with viral pathogenicity.

Download Full-text