scholarly journals Exploring antibody repurposing for COVID-19: beyond presumed roles of therapeutic antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Puneet Rawat ◽  
Divya Sharma ◽  
Ambuj Srivastava ◽  
Vani Janakiraman ◽  
M. Michael Gromiha
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Effective Vaccine ◽  
Therapeutic Antibodies ◽  
Viral Neutralization ◽  
Investigational Drugs ◽  
Therapeutic Monoclonal Antibodies ◽  
Interaction Surface ◽  
Limited Choice

AbstractThe urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.

scholarly journals Broadly-Neutralizing Antibodies Against Emerging SARS-CoV-2 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Lok Bahadur Shrestha ◽  
Nicodemus Tedla ◽  
Rowena A. Bull
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Second Generation ◽  
Therapeutic Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Escape Mutants ◽  
Cross Neutralization ◽  
A Priority ◽  
Therapeutic Monoclonal Antibodies

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have become a major concern in the containment of current pandemic. The variants, including B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta) have shown reduced sensitivity to monoclonal antibodies, plasma and/or sera obtained from convalescent patients and vaccinated individuals. Development of potent therapeutic monoclonal antibodies (mAbs) with broad neutralizing breadth have become a priority for alleviating the devastating effects of this pandemic. Here, we review some of the most promising broadly neutralizing antibodies obtained from plasma of patients that recovered from early variants of SARS-CoV-2 that may be effective against emerging new variants of the virus. This review summarizes several mAbs, that have been discovered to cross-neutralize across Sarbecoviruses and SARS-CoV-2 escape mutants. Understanding the characteristics that confer this broad and cross-neutralization functions of these mAbs would inform on the development of therapeutic antibodies and guide the discovery of second-generation vaccines.

Structurally Mapping Antigenic Epitopes of Adeno-Associated Virus 9: Development of Antibody Escape Variants

2021 ◽  
Author(s):  
Shanan N. Emmanuel ◽  
J. Kennon Smith ◽  
Jane Hsi ◽  
Yu-Shan Tseng ◽  
Matias Kaplan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibodies ◽  
Gene Delivery ◽  
General Population ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Transduction Efficiency ◽  
Viral Neutralization ◽  
Patient Cohort ◽  
Antigenic Epitopes

Adeno-associated viruses (AAV) serve as vectors for therapeutic gene delivery. AAV9 vectors have been FDA approved, as Zolgensma®, for the treatment of spinal muscular atrophy and is being evaluated in clinical trials for the treatment of neurotropic and musculotropic diseases. A major hurdle for AAV-mediated gene delivery is the presence of pre-existing neutralizing antibodies in 40 to 80% of the general population. These pre-existing antibodies can reduce therapeutic efficacy through viral neutralization, and the size of the patient cohort eligible for treatment. In this study, cryo-electron microscopy and image reconstruction was used to define the epitopes of five anti-AAV9 monoclonal antibodies (MAbs); ADK9, HL2368, HL2370, HL2372, and HL2374, on the capsid surface. Three of these, ADK9, HL2370, and HL2374, bound on or near the icosahedral 3-fold axes, HL2368 to the 2/5-fold wall, and HL2372 to the region surrounding the 5-fold axes. Pseudo-atomic modeling enabled the mapping and identification of antibody contact amino acids on the capsid, including S454 and P659. These epitopes overlap with previously defined parvovirus antigenic sites. Capsid amino acids critical for the interactions were confirmed by mutagenesis followed by biochemical assays testing recombinant AAV9 (rAAV9) variants capable of escaping recognition and neutralization by the parental MAbs. These variants retained parental tropism and had similar or improved transduction efficiency compared to AAV9. These engineered rAAV9 variants could expand the patient cohort eligible for AAV9-mediated gene delivery by avoiding pre-existing circulating neutralizing antibodies. IMPORTANCE The use of recombinant AAVs (rAAVs) as delivery vectors for therapeutic genes is becoming increasingly popular, especially following the FDA approval of Luxturna® and Zolgensma®, based on serotypes AAV2 and AAV9, respectively. However, high titer anti-AAV neutralizing antibodies in the general population, exempts patients from treatment. The goal of this study is to circumvent this issue by creating AAV variant vectors not recognized by pre-existing neutralizing antibodies. The mapping of the antigenic epitopes of five different monoclonal antibodies (MAbs) on AAV9, to recapitulate a polyclonal response, enabled the rational design of escape variants with minimal disruption to cell tropism and gene expression. This study, which included four newly developed and now commercially available MAbs, provides a platform for the engineering of rAAV9 vectors that can be used to deliver genes to patients with pre-exiting AAV antibodies.

scholarly journals Therapeutic Monoclonal Antibodies and Antibody Products: Current Practices and Development in Multiple Myeloma

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 15 ◽  
Author(s):  
Francesca Bonello ◽  
Roberto Mina ◽  
Mario Boccadoro ◽  
Francesca Gay
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Plasma Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Promising Target ◽  
Therapeutic Monoclonal Antibodies ◽  
Antibody Drug

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.

scholarly journals Impact of the N501Y substitution of SARS-CoV-2 Spike on neutralizing monoclonal antibodies targeting diverse epitopes

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Cheng ◽  
Shuo Song ◽  
Bing Zhou ◽  
Xiangyang Ge ◽  
Jiazhen Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Binding Affinity ◽  
Neutralizing Antibodies ◽  
Therapeutic Antibodies ◽  
Wild Type ◽  
Neutralization Activity ◽  
Neutralizing Activity ◽  
Rapid Spread ◽  
Global Concern

AbstractThe emergence and rapid spread of the B.1.1.7 lineage (VOC-202012/01) SARS-CoV-2 variant has aroused global concern. The N501Y substitution is the only mutation in the interface between the RBD of B.1.1.7 and ACE2, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we assessed the neutralizing activity and binding affinity of a panel of 12 monoclonal antibodies against the wild type and N501Y mutant SARS-CoV-2 pseudovirus and RBD protein, respectively. We found that the neutralization activity and binding affinity of most detected antibodies (10 out of 12) were unaffected, although the N501Y substitution decreased the neutralizing and binding activities of CB6 and increased that of BD-23. These findings could be of value in the development of therapeutic antibodies.

scholarly journals Adaptive immunity against COVID-19

2020 ◽  
Vol 9 (2) ◽  
pp. 44-46
Author(s):  
Umid Kumar Shrestha
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Adaptive Immunity ◽  
Neutralizing Antibodies ◽  
Rapid Development ◽  
Adaptive Immune Response ◽  
Severe Form ◽  
Viral Neutralization ◽  
The Public ◽  
Adaptive Immune

The adaptive immune response has often been described as the key player in determining the severity of COVID-19 disease. The COVID-19 outcomes seem to be dependent upon the B-cell– and T-cell–mediated adaptive immunity to SARS-CoV-2. Coordinated CD4+ T-cell, CD8+ T-cell, and antibody responses are protective, whereas, the uncoordinated immune responses are associated with the severe form of COVID-19. Multiple human vaccines in clinical trials to counteract SARS-CoV-2 is based upon the neutralizing antibodies directed at the spike protein. The potential therapeutic and preventive monoclonal antibodies used in human clinical trials are also based on the viral neutralization. The vaccines can generate high levels of neutralizing antibodies comparable with or greater than those seen in sera samples from patients. The induction of sufficient CD4+ helper T-cells and inclusion of vaccine boosts, may be needed to maintain levels of anti–SARS-CoV-2 neutralizing antibodies. The COVID-19 vaccines are in rapid development by utilizing the knowledge of adaptive immunity against COVID-19, and we are hopeful to get the effective and safe vaccines for the public use very soon.

scholarly journals Distinct Mechanisms of Neutralization by Monoclonal Antibodies Specific for Sites in the N-Terminal or C-Terminal Domain of Murine Leukemia Virus SU

2003 ◽  
Vol 77 (7) ◽  
pp. 3993-4003 ◽  
Author(s):  
Michael Dominic Burkhart ◽  
Samuel C. Kayman ◽  
Yuxian He ◽  
Abraham Pinter
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Murine Leukemia Virus ◽  
Neutralizing Antibodies ◽  
Leukemia Virus ◽  
Binding Pocket ◽  
Protein Subunit ◽  
Viral Neutralization ◽  
Terminal Domain ◽  
Murine Leukemia

ABSTRACT The epitope specificities and functional activities of monoclonal antibodies (MAbs) specific for the murine leukemia virus (MuLV) SU envelope protein subunit were determined. Neutralizing antibodies were directed towards two distinct sites in MuLV SU: one overlapping the major receptor-binding pocket in the N-terminal domain and the other involving a region that includes the most C-terminal disulfide-bonded loop. Two other groups of MAbs, reactive with distinct sites in the N-terminal domain or in the proline-rich region (PRR), did not neutralize MuLV infectivity. Only the neutralizing MAbs specific for the receptor-binding pocket were able to block binding of purified SU and MuLV virions to cells expressing the ecotropic MuLV receptor, mCAT-1. Whereas the neutralizing MAbs specific for the C-terminal domain did not interfere with the SU-mCAT-1 interaction, they efficiently inhibited cell-to-cell fusion mediated by MuLV Env, indicating that they interfered with a postattachment event necessary for fusion. The C-terminal domain MAbs displayed the highest neutralization titers and binding activities. However, the nonneutralizing PRR-specific MAbs bound to intact virions with affinities similar to those of the neutralizing receptor-binding pocket-specific MAbs, indicating that epitope exposure, while necessary, is not sufficient for viral neutralization by MAbs. These results identify two separate neutralization domains in MuLV SU and suggest a role for the C-terminal domain in a postattachment step necessary for viral fusion.

Immunogenicity and Safety Profile of COVID-19 Vaccines- A Systematic Review (Preprint)

2020 ◽  
Author(s):  
Reeju Maharjan ◽  
Aditya Bamboria ◽  
Neelam Asghar ◽  
Manish Shrestha ◽  
Syed W H Rizvi
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Systematic Reviews ◽  
Neutralizing Antibodies ◽  
Phase Iii ◽  
Effective Vaccine ◽  
Efficacy And Safety ◽  
Vaccine Candidates ◽  
One Year ◽  
Meta Analyses

BACKGROUND An effective vaccine will be important in controlling severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. OBJECTIVE In this study, we aim to analyze the degree of immunogenicity that rises after administering different vaccines, and to study their efficacy. METHODS We systematically reviewed multiple vaccine candidates at different stages of clinical trials to prevent Coronavirus disease in 2019 (COVID-19). We reviewed literature from four major electronic databases (PubMed, MEDLINE, PubMed Central, and Google scholar) to identify studies on SARS-CoV-2 vaccine candidates. This article included studies that include clinical trials in multiple stages and systematic reviews published in 2020. We performed a quality assessment with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our articles. RESULTS We included a total of 19 articles. This review article has a total of 24,342 individuals. These studies show promising results regarding vaccines candidates, safety profiles, and immunogenicity with the effective generation of neutralizing antibodies and specific T-cell responses. Adverse effects range from mild to moderate, with no serious adverse effects reported. It is unclear how long the generated immunity will last, and a follow up of the study participants for an extended one-year period will be needed. CONCLUSIONS Ascertaining vaccines' efficacy and safety in vulnerable populations is essential for the general use of vaccine use. A number of these vaccines are currently under phase III or to enter phase III and may increase vaccines' efficacy and safety in different populations.

scholarly journals Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

2016 ◽  
Vol 90 (10) ◽  
pp. 5031-5046 ◽  
Author(s):  
Navid Madani ◽  
Amy M. Princiotto ◽  
David Easterhoff ◽  
Todd Bradley ◽  
Kan Luo ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Effective Vaccine ◽  
Broadly Neutralizing Antibodies ◽  
Variable Regions ◽  
Hiv 1

ABSTRACTThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

scholarly journals The emergence of SARS-CoV-2 variants threatens to decrease the efficacy of neutralizing antibodies and vaccines

2021 ◽  
Author(s):  
Kensaku Murano ◽  
Youjia Guo ◽  
Haruhiko Siomi
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
The Novel ◽  
Therapeutic Antibodies ◽  
Human Origin ◽  
New Challenges ◽  
Novel Coronavirus

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19) pandemic. As of August 2021, more than 200 million people have been infected with the virus and 4.3 million have lost their lives. Various monoclonal antibodies of human origin that neutralize the SARS-CoV-2 infection have been isolated from convalescent patients for therapeutic and prophylactic purposes. Several vaccines have been developed to restrict the spread of the virus and have been rapidly administered. However, the rollout of vaccines has coincided with the spread of variants of concern. Emerging variants of SARS-CoV-2 present new challenges for therapeutic antibodies and threaten the efficacy of current vaccines. Here, we review the problems faced by neutralizing antibodies and vaccines in the midst of the increasing spread of mutant viruses.

scholarly journals The Relevance of Monoclonal Antibodies in the Treatment of COVID-19

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 557
Author(s):  
Anabel Torrente-López ◽  
Jesús Hermosilla ◽  
Natalia Navas ◽  
Luis Cuadros-Rodríguez ◽  
José Cabeza ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
State Of The Art ◽  
Virus Protein ◽  
Immune Disorders ◽  
The Subject ◽  
New Treatments ◽  
Therapeutic Monoclonal Antibodies ◽  
Made In

Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic monoclonal antibodies (mAbs) have been the subject of widespread investigation focusing on two target-based groups, i.e., non-SARS-CoV-2 specific mAbs, that target immune system responses, and SARS-CoV-2 specific mAbs, designed to neutralize the virus protein structure. Here we review the latest literature about the use of mAbs in order to describe the state of the art of the clinical trials and the benefits of using these biotherapeutics in the treatment of COVID-19. The clinical trials considered in the present review include both observational and randomized studies. We begin by presenting the studies conducted using non-SARS-CoV-2 specific mAbs for treating different immune disorders that were already on the market. Within this group of mAbs, we focus particularly on anti-IL-6/IL-6R. This is followed by a discussion of the studies on SARS-CoV-2 specific mAbs. Our findings indicate that SARS-CoV-2 specific mAbs are significantly more effective than non-specific ones.

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