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1.
Clin Lab ; 67(11)2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1818667

ABSTRACT

BACKGROUND: Immunoglobulin D multiple myeloma (IgD-MM) is a rare but aggressive disease. The safety and effectiveness of anti-CD38 monoclonal antibody (daratumumab) have not been known in either IgD-MM or MM complicated with secondary neoplasm. METHODS: A fragile IgD-MM patient had an aggressively relapsed disease concurrent with lung cancer and severe thrombocytopenia, which led to a dilemma for management. After a failure of ixazomib-based chemotherapy, a salvage therapy with daratumumab unexpectedly induced complete remission and platelet recovery, and the patient successfully proceeded to lung cancer surgery. CONCLUSIONS: Our case indicates daratumumab is both safe and effective for refractory IgD-MM with severe complications.


Subject(s)
Lung Neoplasms , Multiple Myeloma , Thrombocytopenia , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Immunoglobulin D , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Multiple Myeloma/complications , Multiple Myeloma/drug therapy , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy
2.
Commun Biol ; 5(1): 342, 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1784032

ABSTRACT

Three betacoronaviruses have crossed the species barrier and established human-to-human transmission causing significant morbidity and mortality in the past 20 years. The most current and widespread of these is SARS-CoV-2. The identification of CoVs with zoonotic potential in animal reservoirs suggests that additional outbreaks could occur. Monoclonal antibodies targeting conserved neutralizing epitopes on diverse CoVs can form the basis for prophylaxis and therapeutic treatments and enable the design of vaccines aimed at providing pan-CoV protection. We previously identified a neutralizing monoclonal antibody, CV3-25 that binds to the SARS-CoV-2 spike, neutralizes the SARS-CoV-2 Beta variant comparably to the ancestral Wuhan Hu-1 strain, cross neutralizes SARS-CoV-1 and binds to recombinant proteins derived from the spike-ectodomains of HCoV-OC43 and HCoV-HKU1. Here, we show that the neutralizing activity of CV3-25 is maintained against the Alpha, Delta, Gamma and Omicron variants of concern as well as a SARS-CoV-like bat coronavirus with zoonotic potential by binding to a conserved linear peptide in the stem-helix region. Negative stain electron microscopy and a 1.74 Å crystal structure of a CV3-25/peptide complex demonstrates that CV3-25 binds to the base of the stem helix at the HR2 boundary to an epitope that is distinct from other stem-helix directed neutralizing mAbs.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , Epitopes , Spike Glycoprotein, Coronavirus/chemistry
3.
JAMA Netw Open ; 5(4): e226920, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1782544

ABSTRACT

Importance: Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19; however, only intravenous administration has been evaluated in randomized clinical trials of treatment. Subcutaneous administration may expand outpatient treatment capacity and qualified staff available to administer treatment, but the association with patient outcomes is understudied. Objectives: To evaluate whether subcutaneous casirivimab and imdevimab treatment is associated with reduced 28-day hospitalization and death compared with nontreatment among mAb-eligible patients and whether subcutaneous casirivimab and imdevimab treatment is clinically and statistically similar to intravenous casirivimab and imdevimab treatment. Design, Setting, and Participants: This prospective cohort study evaluated high-risk outpatients in a learning health system in the US with mild to moderate COVID-19 symptoms from July 14 to October 26, 2021, who were eligible for mAb treatment under emergency use authorization. A nontreated control group of eligible patients was also studied. Exposures: Subcutaneous injection or intravenous administration of the combined single dose of 600 mg of casirivimab and 600 mg of imdevimab. Main Outcomes and Measures: The primary outcome was the 28-day adjusted risk ratio or adjusted risk difference for hospitalization or death. Secondary outcomes included 28-day adjusted risk ratios and differences in hospitalization, death, a composite end point of emergency department admission and hospitalization, and rates of adverse events. Among 1959 matched adults with mild to moderate COVID-19, 969 patients (mean [SD] age, 53.8 [16.7] years; 547 women [56.4%]) who received casirivimab and imdevimab subcutaneously had a 28-day rate of hospitalization or death of 3.4% (22 of 653 patients) compared with 7.0% (92 of 1306 patients) in nontreated controls (risk ratio, 0.48; 95% CI, 0.30-0.80; P = .002). Among 2185 patients treated with subcutaneous (n = 969) or intravenous (n = 1216; mean [SD] age, 54.3 [16.6] years; 672 women [54.4%]) casirivimab and imdevimab, the 28-day rate of hospitalization or death was 2.8% vs 1.7%, which resulted in an adjusted risk difference of 1.5% (95% CI, -0.6% to 3.5%; P = .16). Among all infusion patients, there was no difference in intensive care unit admission (adjusted risk difference, 0.7%; 95% CI, -3.5% to 5.0%) or need for mechanical ventilation (adjusted risk difference, 0.2%; 95% CI, -5.8% to 5.5%). Conclusions and Relevance: In this cohort study of high-risk outpatients with mild to moderate COVID-19 symptoms, subcutaneously administered casirivimab and imdevimab was associated with reduced hospitalization and death when compared with no treatment. These results provide preliminary evidence of potential expanded use of subcutaneous mAb treatment, particularly in areas that are facing treatment capacity and/or staffing shortages.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Cohort Studies , Female , Humans , Infusions, Intravenous , Middle Aged , Prospective Studies , SARS-CoV-2
4.
Signal Transduct Target Ther ; 7(1): 114, 2022 Apr 05.
Article in English | MEDLINE | ID: covidwho-1778593

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel coronavirus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.


Subject(s)
Antibodies, Monoclonal , Antibodies, Viral , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Antibodies, Monoclonal/chemistry , Antibodies, Viral/chemistry , COVID-19 , Cryoelectron Microscopy , Humans , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
5.
J Med Virol ; 94(5): 2222-2229, 2022 May.
Article in English | MEDLINE | ID: covidwho-1777590

ABSTRACT

To assess the clinical efficacy and safety of neutralizing monoclonal antibodies (mABs) for outpatients with coronavirus disease 2019 (COVID-19). PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) databases were searched from inception to July 19, 2021. Only randomized controlled trials (RCTs) that assessed the clinical efficacy and safety of neutralizing mABs in the treatment of COVID-19 outpatients were included. The Cochrane risk-of-bias tool was used to assess the quality of the included RCTs. The primary outcome was the risk of COVID-19-related hospitalization or emergency department (ED) visits. The secondary outcomes were the risk of death and adverse events (AEs). Five articles were included, in which 3309 patients received neutralizing mAB and 2397 patients received a placebo. A significantly lower rate of hospitalization or ED visits was observed among patients who received neutralizing mABs than those who received a placebo (1.7% vs. 6.5%, odds ratios (OR): 0.26; 95% confidence interval (CI): 0.19-0.36; I2 = 0%). In addition, the rate of hospitalization was significantly lower in the patients who received neutralizing mABs than in the control group (OR: 0.24; 95% CI: 0.17-0.34; I2 = 0%). The mortality rate was also significantly lower in the patients who received neutralizing mABs than in the control group (OR: 0.16; 95% CI: 0.05-0.58; I2 = 3%). Neutralizing mABs were associated with a similar risk of any AE (OR: 0.81; 95% CI: 0.64-1.01; I2 = 52%) and a lower risk of serious AEs (OR: 0.37; 97% CI: 0.19-0.72; I2 = 45%) compared with a placebo. Neutralizing mABs can help reduce the risk of hospitalization or ED visits in COVID-19 outpatients. For these patients, neutralizing mABs are safe and not associated with a higher risk of AEs than a placebo.


Subject(s)
COVID-19 , Antibodies, Monoclonal/adverse effects , Antibodies, Neutralizing/therapeutic use , COVID-19/drug therapy , Humans , Outpatients , Randomized Controlled Trials as Topic
7.
Kidney360 ; 3(1): 133-143, 2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1776876

ABSTRACT

Background: Morbidity and mortality associated with coronavirus disease 2019 (COVID-19) infection in kidney transplant recipients are high and early outpatient interventions to prevent progression to severe disease are needed. SARS-CoV-2 neutralizing mAbs, including bamlanivimab and casirivimab-imdevimab, received emergency use authorization in the United States in November 2020 for treatment of mild to moderate COVID-19 disease. Methods: We performed a retrospective analysis of 27 kidney transplant recipients diagnosed with COVID-19 between July 2020 and February 2021 who were treated with bamlanivimab or casirivimab-imdevimab and immunosuppression reduction. We additionally identified 13 kidney transplant recipients with COVID-19 who had mild to moderate disease at presentation, who did not receive mAbs, and had SARS-CoV-2 serology testing available. Results: There were no deaths or graft failures in either group. Both infusions were well tolerated. Four of the 27 patients treated with mAbs required hospitalization due to COVID-19. Four of 13 patients who did not receive mAbs required hospitalization due to COVID-19. Patients who received mAbs demonstrated measurable anti-SARS-CoV-2 IgG with angiotensin-converting enzyme 2 (ACE2) receptor blocking activity at the highest level detectable at 90 days postinfusion, whereas ACE2 blocking activity acquired from natural immunity in the mAb-untreated group was weak. Conclusions: Bamlanivimab and casirivimab-imdevimab combined with immunosuppression reduction were well tolerated and associated with favorable clinical outcomes in kidney transplant recipients diagnosed with mild to moderate COVID-19.


Subject(s)
COVID-19 , Kidney Transplantation , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Humans , Retrospective Studies , SARS-CoV-2
8.
Zhonghua Jie He He Hu Xi Za Zhi ; 45(4): 341-354, 2022 Apr 12.
Article in Chinese | MEDLINE | ID: covidwho-1776389

ABSTRACT

As the first targeted biotherapy for asthma, Omalizumab, was officially approved in China in August 2017, and was applied in clinical practice since March, 2018. Dozens of experts in Respirology and Allergy from China fully discussed the important clinical issues on the use of Omalizumab in allergic asthma by referring to the relevant publications over the world and the first version of consensus published in March 2018. Until now, over 30, 000 allergic asthma patients have received the treatment of Omalizumab. Therefore, with the latest evidence of clinical and basic research around the world, we updated the consensus with the following issues: (1) The mechanisms and available evidence on anti-IgE treatment; (2) Selection and exclusion criteria for patients using Omalizumab; (3) Cautions on the administration of Omalizumab and highlights of the use of Omalizumab with various vaccines, including novel Coronavirus vaccines, and key points to note during a Novel Coronavirus pandemic; (4) Long-term use and safety; (5) The use of Omalizumab in specific populations; (6) Clinical applications of omalizumab with other targeted therapies and allergen-specific immunotherapy. Omalizumab, combining to the Cε3 area of IgE, reduces the free IgE level, and downregulates the expression of FcεRⅠ, which inhibits the release of inflammatory mediators of mast cell sources, and leads to reduced asthma exacerbation, decreased rate of emergency visit and hospitalization, improved symptoms and quality of life, as well as less concomitant moderate to severe asthma, poorly controlled after at least 3 months treatment of ICS/LABA, and confirmed with allergic status through skin prick test or serum total IgE or specific IgE. Conditions that exclude the use of Omalizumab include patients who are suspected to be allergic to drug ingredients. Omalizumab is administered based on dosing tables by subcutaneous injection. Omalizumab should be administered by a health care professional (doctor or nurse) in a medical institution equipped with facilities for post-injection observation and rescue treatment for anaphylactic shock. After the injection, the patient should be closely monitored whether there is an anaphylactic reaction. The duration of Omalizumab treatment should be at least 16 weeks to judge its effectiveness, after 16 weeks, Omalizumab treatment will be continued or withdrawn based on the overall asthma control evaluation. Patients should be followed every 3 months to assess the disease control and dosing adjustment. The common adverse reactions were injection sites reactions. Based on the latest evidence around the word, we focused on updating the relevant treatment course, administration method and use of specific populations, in order to guide clinicians in the use of Omalizumab. The use of Omalizumab in China still requires long-term observation and further research. With the increase of clinical evidence, this consensus will be continuously improved and supplemented.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Anti-Asthmatic Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Asthma/drug therapy , Consensus , Humans , Omalizumab/therapeutic use , Quality of Life
9.
Front Public Health ; 10: 712657, 2022.
Article in English | MEDLINE | ID: covidwho-1775961

ABSTRACT

Listeria monocytogenes is the causative agent of listeriosis, a highly lethal disease initiated after the ingestion of Listeria-contaminated food. This species comprises different serovars, from which 4b, 1/2a, and 1/2b cause most of the infections. Among the different proteins involved in pathogenesis, the internalins A (InlA) and B (InlB) are the best characterized, since they play a major role in the enterocyte entry of Listeria cells during early infection. Due to their covalent attachment to the cell wall and location on the bacterial surface, along with their exclusive presence in the pathogenic L. monocytogenes, these proteins are also used as detection targets for this species. Even though huge advancements were achieved in the enrichment steps for subsequent Listeria detection, few studies have focused on the improvement of the antibodies for immunodetection. In the present study, recombinant InlA and InlB produced in Escherichia coli were used as targets to generate antibodies via phage display using the human naïve antibody libraries HAL9 and HAL10. A set of five recombinant antibodies (four against InlA, and one against InlB) were produced in scFv-Fc format and tested in indirect ELISA against a panel of 19 Listeria strains (17 species; including the three main serovars of L. monocytogenes) and 16 non-Listeria species. All five antibodies were able to recognize L. monocytogenes with 100% sensitivity (CI 29.24-100.0) and specificity (CI 88.78-100.0) in all three analyzed antibody concentrations. These findings show that phage display-derived antibodies can improve the biological tools to develop better immunodiagnostics for L. monocytogenes.


Subject(s)
Antibodies, Monoclonal , Bacterial Proteins , Listeria monocytogenes , Antibodies, Monoclonal/metabolism , Bacterial Proteins/immunology , Bacteriophages , Cell Surface Display Techniques , Humans , Listeria monocytogenes/isolation & purification
10.
Front Immunol ; 13: 836232, 2022.
Article in English | MEDLINE | ID: covidwho-1775668

ABSTRACT

The continuous emergence of SARS-coronavirus 2 (SARS-CoV-2) variants, especially the variants of concern (VOC), exacerbated the impact of the coronavirus disease 2019 (COVID-19) pandemic. As the key of viral entry into host cells, the spike (S) protein is the major target of therapeutic monoclonal antibodies (mAbs) and polyclonal antibodies elicited by infection or vaccination. However, the mutations of S protein in variants may change the infectivity and antigenicity of SARS-CoV-2, leading to the immune escape from those neutralizing antibodies. To characterize the mutations of S protein in newly emerging variants, the proteolytic property and binding affinity with receptor were assessed, and the vesicular stomatitis virus (VSV)-based pseudovirus system was used to assess the infectivity and immune escape. We found that some SARS-CoV-2 variants have changed significantly in viral infectivity; especially, B.1.617.2 is more likely to infect less susceptible cells than D614G, and the virus infection process can be completed in a shorter time. In addition, neutralizing mAbs and vaccinated sera partially or completely failed to inhibit host cell entry mediated by the S protein of certain SARS-CoV-2 variants. However, SARS-CoV-2 variant S protein-mediated viral infection can still be blocked by protease inhibitors and endocytosis inhibitors. This work provides a deeper understanding of the rise and evolution of SARS-CoV-2 variants and their immune evasion.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Antibodies, Neutralizing , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
13.
PLoS Negl Trop Dis ; 16(3): e0010311, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1770641

ABSTRACT

BACKGROUND: The focus on laboratory-based diagnosis of coronavirus disease 2019 (COVID-19) warrants alternative public health tools such as rapid antigen tests. While there are a number of commercially available antigen tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), all cross-react with the genetically similar SARS-CoV-1 or require an instrument for results interpretation. METHODOLOGY/PRINCIPAL FINDINGS: We developed and validated rapid antigen tests that use pairs of murine-derived monoclonal antibodies (mAbs), along with gold nanoparticles, to detect SARS-CoV-2 with or without cross-reaction to SARS-CoV-1 and other coronaviruses. In this development, we demonstrate a robust antibody screening methodology for the selection of mAb pairs that can recognize SARS-CoV-2 spike (S) and nucleocapsid (N) proteins. Linear epitope mapping of the mAbs helped elucidate SARS-CoV-2 S and N interactions in lateral flow chromatography. A candidate rapid antigen test for SARS-CoV-2 N was validated using nasal swab specimens that were confirmed positive or negative by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Test results were image-captured using a mobile phone and normalized signal pixel intensities were calculated; signal intensities were inversely correlated to RT-PCR cycle threshold (Ct) value. CONCLUSION/SIGNIFICANCE: Overall, our results suggest that the rapid antigen test is optimized to detect SARS-CoV-2 N during the acute phase of COVID-19. The rapid antigen tests developed in this study are alternative tools for wide scale public health surveillance of COVID-19.


Subject(s)
COVID-19 , Metal Nanoparticles , Animals , Antibodies, Monoclonal , COVID-19/diagnosis , Gold , Mice , SARS-CoV-2 , Sensitivity and Specificity
14.
Indian J Pharmacol ; 54(1): 51-57, 2022.
Article in English | MEDLINE | ID: covidwho-1766048

ABSTRACT

The use of monoclonal antibodies has expanded beyond the realm of autoimmune disease and cancer therapeutics to communicable diseases. Their antiviral activities were evaluated in some diseases such as SARS MERS (Middle East Respiratory Syndrome) and Ebola. In recent times, antispike SARS-CoV-2 monoclonal antibody cocktails (casirivimab with imdevimab and bamlanivimab with etesevimab) and single agent sotrovimab have received emergency use authorization for treatment of nonhospitalized COVID-19 patients with mild-to-moderate disease at high risk of disease progression. This review summarizes their mechanism of action, salient pharmacokinetic profile, safety and clinical trial (ongoing and completed) data. Despite evidence to support its use for the indication, the high cost of these biologics may make it unaffordable for many patients, but further clinical studies on their cost-benefit profile shall provide useful information to the scientific community and patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , COVID-19/drug therapy , Humans
15.
Sci Adv ; 8(12): eabm0220, 2022 03 25.
Article in English | MEDLINE | ID: covidwho-1765069

ABSTRACT

Conventional approaches to isolate and characterize nanobodies are laborious. We combine phage display, multivariate enrichment, next-generation sequencing, and a streamlined screening strategy to identify numerous anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nanobodies. We characterize their potency and specificity using neutralization assays and hydrogen/deuterium exchange mass spectrometry (HDX-MS). The most potent nanobodies bind to the receptor binding motif of the receptor binding domain (RBD), and we identify two exceptionally potent members of this category (with monomeric half-maximal inhibitory concentrations around 13 and 16 ng/ml). Other nanobodies bind to a more conserved epitope on the side of the RBD and are able to potently neutralize the SARS-CoV-2 founder virus (42 ng/ml), the Beta variant (B.1.351/501Y.V2) (35 ng/ml), and also cross-neutralize the more distantly related SARS-CoV-1 (0.46 µg/ml). The approach presented here is well suited for the screening of phage libraries to identify functional nanobodies for various biomedical and biochemical applications.


Subject(s)
COVID-19 , Camelids, New World , Single-Domain Antibodies , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Viral , Camelids, New World/metabolism , Humans , Membrane Glycoproteins , Neutralization Tests , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins/metabolism
17.
J Biotechnol ; 349: 53-64, 2022 Apr 10.
Article in English | MEDLINE | ID: covidwho-1757476

ABSTRACT

In recent years, acceleration of development timelines has become a major focus within the biopharmaceutical industry to bring innovative therapies faster to patients. However, in order to address a high unmet medical need even faster further acceleration potential has to be identified to transform "speed-to-clinic" concepts into "warp-speed" development programs. Recombinant Chinese hamster ovary (CHO) cell lines are the predominant expression system for monoclonal antibodies (mAbs) and are routinely generated by random transgene integration (RTI) of the genetic information into the host cell genome. This process, however, exhibits considerable challenges such as the requirement for a time-consuming clone screening process to identify a suitable clonally derived manufacturing cell line. Hence, RTI represents an error prone and tedious method leading to long development timelines until availability of Good Manufacturing Practice (GMP)-grade drug substance (DS). Transposase-mediated semi-targeted transgene integration (STI) has been recently identified as a promising alternative to RTI as it allows for a more rapid generation of high-performing and stable production cell lines. In this report, we demonstrate how a STI technology was leveraged to develop a very robust DS manufacturing process based on a stable pool cell line at unprecedented pace. Application of the novel strategy resulted in the manufacturing of GMP-grade DS at 2,000 L scale in less than three months paving the way for a start of Phase I clinical trials only six months after transfection. Finally, using a clonally derived production cell line, which was established from the parental stable pool, we were able to successfully implement a process with an increased mAb titer of up to 5 g per liter at the envisioned commercial scale (12,000 L) within eight months.


Subject(s)
Antibodies, Monoclonal , Sexually Transmitted Diseases , Acceleration , Animals , CHO Cells , Cricetinae , Cricetulus , Humans , Sexually Transmitted Diseases/drug therapy , Transposases
18.
Antiviral Res ; 201: 105297, 2022 May.
Article in English | MEDLINE | ID: covidwho-1757112

ABSTRACT

Monoclonal antibody therapy is a promising option for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and a cocktail of antibodies (REGN-COV) has been administered to infected patients with a favorable outcome. However, it is necessary to continue generating novel sets of monoclonal antibodies with neutralizing activity because viral variants can emerge that show resistance to the currently utilized antibodies. Here, we isolated a new cocktail of antibodies, EV053273 and EV053286, from peripheral blood mononuclear cells derived from convalescent patients infected with wild-type SARS-CoV-2. EV053273 exerted potent antiviral activity against the Wuhan wild-type virus as well as the Alpha and Delta variants in vitro, whereas the antiviral activity of EV053286 was moderate, but it had a wide-range of suppressive activity on the wild-type virus as well as the Alpha, Beta, Delta, Kappa, Omicron BA.1, and BA.2 variants. With the combined use of EV053273 and EV053286, we observed similar inhibitory effects on viral replication as with REGN-COV in vitro. We further assessed their activity in vivo by using a mouse model infected with a recently established viral strain with adopted infectious activity in mice. Independent experiments revealed that the combined use of EV053273 and EV053286 or the single use of each monoclonal antibody efficiently blocked infection in vivo. Together with data showing that these two monoclonal antibodies could neutralize REGN-COV escape variants and the Omicron variant, our findings suggest that the EV053273 and EV053286 monoclonal antibody cocktail is a novel clinically applicable therapeutic candidate for SARS-CoV-2 infection.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Combinations , Humans , Leukocytes, Mononuclear , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
19.
Viruses ; 14(3)2022 03 21.
Article in English | MEDLINE | ID: covidwho-1753692

ABSTRACT

There is a growing interest in using monoclonal antibodies (mAbs) in the early stages of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection to prevent disease progression. Little is known about the efficacy of mAbs against the delta variant of concern and its clinical presentations. We evaluated the effect of casirivimab/imdevimab treatment among five delta vaccine breakthrough patients. Symptomatic non-hospitalized vaccinated patients were submitted to nasopharyngeal swabs for the detection of SARS-CoV-2 and Next-Generation Sequencing (NGS). Blood analysis and chest Computed Tomography were also performed. A cocktail of casirivimab/imdevimab was administrated, and patients were monitored weekly. Clinical evolution was evaluated by the regression of the symptoms, negative results by real-time RT-PCR, and by the need of hospitalization: these aspects were considered as significant outcomes. In four cases, symptom reversion and viral load reduction were observed within 2 days and 7 days after mAbs treatment, respectively. Only one case, suffering from thymoma, was hospitalized 2 days later because of respiratory failure, which reverted within 18 days. mAbs treatment seems to be safe and effective against the delta variant and its clinical manifestations.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , SARS-CoV-2/genetics
20.
Sci Rep ; 12(1): 4683, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1751758

ABSTRACT

The emergence and rapid spread of the Omicron variant of SARS-CoV-2, which has more than 30 substitutions in the spike glycoprotein, compromises the efficacy of currently available vaccines and therapeutic antibodies. Using a clinical strain of the Omicron variant, we analyzed the neutralizing power of eight currently used monoclonal antibodies compared to the ancestral B.1 BavPat1 D614G strain. We observed that six of these antibodies have lost their ability to neutralize the Omicron variant. Of the antibodies still having neutralizing activity, Sotrovimab/Vir-7831 shows the smallest reduction in activity, with a factor change of 3.1. Cilgavimab/AZD1061 alone shows a reduction in efficacy of 15.8, resulting in a significant loss of activity for the Evusheld cocktail (42.6-fold reduction) in which the other antibody, Tixagevimab, does not retain significant activity against Omicron. Our results suggest that the clinical efficacy of the initially proposed doses should be rapidly evaluated and the possible need to modify doses or propose combination therapies should be considered.


Subject(s)
COVID-19 , Viral Envelope Proteins , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , Humans , Membrane Glycoproteins , Neutralization Tests , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
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