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Annals of Internal Medicine Jun 2021The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear. (Review)
Review
BACKGROUND
The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear.
PURPOSE
To synthesize evidence on the prevalence, levels, and durability of detectable antibodies after SARS-CoV-2 infection and whether antibodies to SARS-CoV-2 confer natural immunity.
DATA SOURCES
MEDLINE (Ovid), Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, World Health Organization global literature database, and Covid19reviews.org from 1 January through 15 December 2020, limited to peer-reviewed publications available in English.
STUDY SELECTION
Primary studies characterizing the prevalence, levels, and duration of antibodies in adults with SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR); reinfection incidence; and unintended consequences of antibody testing.
DATA EXTRACTION
Two investigators sequentially extracted study data and rated quality.
DATA SYNTHESIS
Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection with SARS-CoV-2 and that IgG levels peak approximately 25 days after symptom onset and may remain detectable for at least 120 days. Moderate-strength evidence suggests that IgM levels peak at approximately 20 days and then decline. Low-strength evidence suggests that most adults generate neutralizing antibodies, which may persist for several months like IgG. Low-strength evidence also suggests that older age, greater disease severity, and presence of symptoms may be associated with higher antibody levels. Some adults do not develop antibodies after SARS-CoV-2 infection for reasons that are unclear.
LIMITATIONS
Most studies were small and had methodological limitations; studies used immunoassays of variable accuracy.
CONCLUSION
Most adults with SARS-CoV-2 infection confirmed by RT-PCR develop antibodies. Levels of IgM peak early in the disease course and then decline, whereas IgG peaks later and may remain detectable for at least 120 days.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).
Topics: Antibodies, Viral; Antibody Formation; Antibody Specificity; COVID-19; Humans; Immunoglobulin G; Immunoglobulin M; Pneumonia, Viral; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2; Sensitivity and Specificity
PubMed: 33721517
DOI: 10.7326/M20-7547 -
MAbs 2021Antibody-based drugs, which now represent the dominant biologic therapeutic modality, are used to modulate disparate signaling pathways across diverse disease... (Review)
Review
Antibody-based drugs, which now represent the dominant biologic therapeutic modality, are used to modulate disparate signaling pathways across diverse disease indications. One fundamental premise that has driven this therapeutic antibody revolution is the belief that each monoclonal antibody exhibits exquisitely specific binding to a single-drug target. Herein, we review emerging evidence in antibody off-target binding and relate current key findings to the risk of failure in therapeutic development. We further summarize the current state of understanding of structural mechanisms underpining the different phenomena that may drive polyreactivity and polyspecificity, and highlight current thinking on how de-risking studies may be best implemented in the screening triage. We conclude with a summary of what we believe to be key observations in the field to date, and a call for the wider antibody research community to work together to build the tools needed to maximize our understanding in this nascent area.
Topics: Antibodies, Monoclonal; Antibody Specificity; Risk Factors
PubMed: 34780320
DOI: 10.1080/19420862.2021.1999195 -
Science Translational Medicine Jul 2021Although substantial progress has been made with Ebola virus (EBOV) vaccine measures, the immune correlates of vaccine-mediated protection remain uncertain. Here, five...
Although substantial progress has been made with Ebola virus (EBOV) vaccine measures, the immune correlates of vaccine-mediated protection remain uncertain. Here, five mucosal vaccine vectors based on human and avian paramyxoviruses provided nonhuman primates with varying degrees of protection, despite expressing the same EBOV glycoprotein (GP) immunogen. Each vaccine produced antibody responses that differed in Fc-mediated functions and isotype composition, as well as in magnitude and coverage toward GP and its conformational and linear epitopes. Differences in the degree of protection and comprehensive characterization of the response afforded the opportunity to identify which features and functions were elevated in survivors and could therefore serve as vaccine correlates of protection. Pairwise network correlation analysis of 139 immune- and vaccine-related parameters was performed to demonstrate relationships with survival. Total GP-specific antibodies, as measured by biolayer interferometry, but not neutralizing IgG or IgA titers, correlated with survival. Fc-mediated functions and the amount of receptor binding domain antibodies were associated with improved survival outcomes, alluding to the protective mechanisms of these vaccines. Therefore, functional qualities of the antibody response, particularly Fc-mediated effects and GP specificity, rather than simply magnitude of the response, appear central to vaccine-induced protection against EBOV. The heterogeneity of the response profile between the vaccines indicates that each vaccine likely exhibits its own protective signature and the requirements for an efficacious EBOV vaccine are complex.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antibody Specificity; Ebola Vaccines; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Primates
PubMed: 34261800
DOI: 10.1126/scitranslmed.abg6128 -
The Journal of Comparative Neurology Aug 2018α-Synuclein (α-syn) is an abundant presynaptic protein that is the primary constituent of inclusions that define Lewy body diseases (LBDs). In these inclusions, α-syn...
α-Synuclein (α-syn) is an abundant presynaptic protein that is the primary constituent of inclusions that define Lewy body diseases (LBDs). In these inclusions, α-syn is phosphorylated at the serine-129 residue. Antibodies directed to this phosphorylation site are used to measure inclusion abundance and stage disease progression in preclinical models as well as in postmortem tissues in LBDs. While it is critical to reliably identify inclusions, phospho-specific antibodies often cross-react with nonspecific antigens. Four commercially available monoclonal antibodies, two from rabbits (clones EP1536Y and MJF-R13) and two from mice (81a and pSyn#64), have been the most widely used in detecting pS129-α-syn inclusions. Here, we systematically evaluated these antibodies in brain sections and protein lysates from rats and mice. All antibodies detected pS129-α-syn inclusions in the brain that were induced by preformed α-syn fibrils in wild-type rats and mice. Antibody titrations revealed that clones EP1536Y and 81a comparably labeled inclusions in both the perikarya and neuronal processes in contrast to clones MJF-R13 and pSyn#64 that incompletely labeled inclusions at various antibody concentrations. Except for EP1536Y, the clones produced nonspecific diffuse neuropil labeling in α-syn knockout mice as well as mice and rats injected with monomeric α-syn, with some nonspecific staining titrating with pS129-α-syn inclusions. By immunoblot, all the clones cross-reacted with proteins other than α-syn, warranting caution in interpretations of specificity. Clone EP1536Y uniquely and robustly detected endogenous pS129-α-syn in highly soluble protein fractions from the mouse brain. In summary, EP1536Y had the highest sensitivity and specificity for detecting pS129-α-syn.
Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Brain; Mice; Mice, Inbred C57BL; Rats; Rats, Sprague-Dawley; alpha-Synuclein
PubMed: 29888794
DOI: 10.1002/cne.24468 -
Bioconjugate Chemistry Aug 2014We report on a chemical platform to generate site-specific, homogeneous, antibody-antibody conjugates by targeting and bridging disulfide bonds. A bispecific antibody...
We report on a chemical platform to generate site-specific, homogeneous, antibody-antibody conjugates by targeting and bridging disulfide bonds. A bispecific antibody construct was produced in good yield through simple reduction and bridging of antibody fragment disulfide bonds, using a readily synthesized bis-dibromomaleimide cross-linker. Binding activity of antibodies was maintained, and in vitro binding of target antigens was observed. This technology is demonstrated through linking scFv and Fab antibody fragments, showing its potential for the construction of a diverse range of bispecifics.
Topics: Antibody Specificity; Disulfides; Protein Multimerization; Protein Structure, Quaternary; Single-Chain Antibodies; Substrate Specificity
PubMed: 25033024
DOI: 10.1021/bc5002467 -
International Journal of Molecular... Feb 2018Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the... (Review)
Review
Rheumatoid arthritis (RA) is a polygenic and multifactorial syndrome. Many complex immunological and genetic interactions are involved in the final outcome of the clinical disease. Autoantibodies (rheumatoid factors, anti-citrullinated peptide/protein antibodies) are present in RA patients' sera for a long time before the onset of clinical disease. Prior to arthritis onset, in the autoantibody response, epitope spreading, avidity maturation, and changes towards a pro-inflammatory Fc glycosylation phenotype occurs. Genetic association of epitope specific autoantibody responses and the induction of inflammation dependent and independent changes in the cartilage by pathogenic autoantibodies emphasize the crucial contribution of antibody-initiated inflammation in RA development. Targeting IgG by glyco-engineering, bacterial enzymes to specifically cleave IgG/alter N-linked Fc-glycans at Asn 297 or blocking the downstream effector pathways offers new avenues to develop novel therapeutics for arthritis treatment.
Topics: Animals; Anti-Citrullinated Protein Antibodies; Antibody Specificity; Antigen-Antibody Complex; Antirheumatic Agents; Arthritis; Autoantibodies; Autoantigens; Cartilage Oligomeric Matrix Protein; Collagen Type II; Epitopes; Glucose-6-Phosphate Isomerase; Glycosylation; Humans; Immunoglobulin G; Molecular Targeted Therapy; Pain; Signal Transduction
PubMed: 29495570
DOI: 10.3390/ijms19030677 -
RMD Open Jan 2020High-risk patients with antiphospholipid syndrome (APS) experience increased risk of thrombosis when treated with direct oral anticoagulant (DOAC) therapy compared with... (Review)
Review
High-risk patients with antiphospholipid syndrome (APS) experience increased risk of thrombosis when treated with direct oral anticoagulant (DOAC) therapy compared with warfarin. It is essential to establish the APS diagnosis to choose therapy and determine treatment duration. It requires testing for antiphospholipid antibodies, including lupus anticoagulant (LAC). In this viewpoint, we discuss the options for timing of LAC testing, which includes testing before starting anticoagulant treatment (DOAC or warfarin), after switching to heparin or after withdrawal of anticoagulant treatment. DOACs interfere with LAC testing and recommendations emerge stating not to conduct on-therapy LAC testing. All approaches are to some extent currently practised, but have limitations and the area is therefore seemingly a catch 22. We put forward that the anticoagulant effect of DOAC can be eliminated in the laboratory and therefore patients can be tested on-therapy. While it may not eliminate all cases of interference, it could aid the interpretation in these situations and this approach is attractive from the patient and clinician's perspective. Nevertheless, to prevent misdiagnosis the diagnostic workup for APS requires collaboration between the clinician and the laboratory. We advocate for standardisation in laboratory and clinical practice when diagnosing APS.
Topics: Antibodies, Antiphospholipid; Antibody Specificity; Anticoagulants; Antiphospholipid Syndrome; DiGeorge Syndrome; Diagnosis, Differential; Humans
PubMed: 32144138
DOI: 10.1136/rmdopen-2019-001156 -
Theranostics 2019Therapeutic antibodies are one most significant advances in immunotherapy, the development of antibodies against disease-associated MHC-peptide complexes led to the... (Review)
Review
Therapeutic antibodies are one most significant advances in immunotherapy, the development of antibodies against disease-associated MHC-peptide complexes led to the introduction of TCR-like antibodies. TCR-like antibodies combine the recognition of intracellular proteins with the therapeutic potency and versatility of monoclonal antibodies (mAb), offering an unparalleled opportunity to expand the repertoire of therapeutic antibodies available to treat diseases like cancer. This review details the current state of TCR-like antibodies and describes their production, mechanisms as well as their applications. In addition, it presents an insight on the challenges that they must overcome in order to become commercially and clinically validated.
Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Humans; Immunotherapy; Neoplasms; Receptors, Antigen, T-Cell
PubMed: 31695801
DOI: 10.7150/thno.35486 -
Immunological Reviews Mar 2016Natural immunoglobulin derived from innate-like B lymphocytes plays important roles in the suppression of inflammatory responses and represents a promising therapeutic... (Review)
Review
Natural immunoglobulin derived from innate-like B lymphocytes plays important roles in the suppression of inflammatory responses and represents a promising therapeutic target in a growing number of allergic and autoimmune diseases. These antibodies are commonly autoreactive and incorporate evolutionarily conserved specificities, including certain glycan-specific antibodies. Despite this conservation, exposure to bacterial polysaccharides during innate-like B lymphocyte development, through either natural exposure or immunization, induces significant changes in clonal representation within the glycan-reactive B cell pool. Glycan-reactive natural antibodies (NAbs) have been reported to play protective and pathogenic roles in autoimmune and inflammatory diseases. An understanding of the composition and functions of a healthy glycan-reactive NAb repertoire is therefore paramount. A more thorough understanding of NAb repertoire development holds promise for the design of both biological diagnostics and therapies. In this article, we review the development and functions of NAbs and examine three glycan specificities, represented in the innate-like B cell pool, to illustrate the complex roles environmental antigens play in NAb repertoire development. We also discuss the implications of increased clonal plasticity of the innate-like B cell repertoire during neonatal and perinatal periods, and the prospect of targeting B cell development with interventional therapies and correct defects in this important arm of the adaptive immune system.
Topics: Animals; Antibodies; Antibody Formation; Antibody Specificity; Antigens; B-Lymphocyte Subsets; Cell Differentiation; Clonal Selection, Antigen-Mediated; Epitopes; Gene Rearrangement, B-Lymphocyte; Humans; Immunity, Innate; Immunotherapy; Microbiota; Polysaccharides; Symbiosis
PubMed: 26864103
DOI: 10.1111/imr.12397 -
MAbs 2021Antibodies against coronavirus spike protein potently protect against infection and disease, but whether such protection can be extended to variant coronaviruses is...
Antibodies against coronavirus spike protein potently protect against infection and disease, but whether such protection can be extended to variant coronaviruses is unclear. This is exemplified by a set of iconic and well-characterized monoclonal antibodies developed after the 2003 SARS outbreak, including mAbs m396, CR3022, CR3014 and 80R, which potently neutralize SARS-CoV-1, but not SARS-CoV-2. Here, we explore antibody engineering strategies to change and broaden their specificity, enabling nanomolar binding and potent neutralization of SARS-CoV-2. Intriguingly, while many of the matured clones maintained specificity of the parental antibody, new specificities were also observed, which was further confirmed by X-ray crystallography and cryo-electron microscopy, indicating that a limited set of VH antibody domains can give rise to variants targeting diverse epitopes, when paired with a diverse VL repertoire. Our findings open up over 15 years of antibody development efforts against SARS-CoV-1 to the SARS-CoV-2 field and outline general principles for the maturation of antibody specificity against emerging viruses.
Topics: Antibodies, Neutralizing; Antibodies, Viral; Antibody Specificity; COVID-19; Cross Reactions; Humans; Mutagenesis, Site-Directed; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2
PubMed: 34024246
DOI: 10.1080/19420862.2021.1922134