human monoclonal antibodies
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2022 ◽  
Vol 12 ◽  
Author(s):  
Nabarun Chandra Das ◽  
Pritha Chakraborty ◽  
Jagadeesh Bayry ◽  
Suprabhat Mukherjee

Since the start of the pandemic, SARS-CoV-2 has already infected more than 250 million people globally, with more than five million fatal cases and huge socio-economic losses. In addition to corticosteroids, and antiviral drugs like remdesivir, various immunotherapies including monoclonal antibodies (mAbs) to S protein of SARS-CoV-2 have been investigated to treat COVID-19 patients. These mAbs were initially developed against the wild-type SARS-CoV-2; however, emergence of variant forms of SARS-CoV-2 having mutations in the spike protein in several countries including India raised serious questions on the potential use of these mAbs against SARS-CoV-2 variants. In this study, using an in silico approach, we have examined the binding abilities of eight mAbs against several SARS-CoV-2 variants of Alpha (B.1.1.7) and Delta (B.1.617.2) lineages. The structure of the Fab region of each mAb was designed in silico and subjected to molecular docking against each mutant protein. mAbs were subjected to two levels of selection based on their binding energy, stability, and conformational flexibility. Our data reveal that tixagevimab, regdanvimab, and cilgavimab can efficiently neutralize most of the SARS-CoV-2 Alpha strains while tixagevimab, bamlanivimab, and sotrovimab can form a stable complex with the Delta variants. Based on these data, we have designed, by in silico, a chimeric antibody by conjugating the CDRH3 of regdanivimab with a sotrovimab framework to combat the variants that could potentially escape from the mAb-mediated neutralization. Our finding suggests that though currently available mAbs could be used to treat COVID-19 caused by the variants of SARS-CoV-2, better results could be expected with the chimeric antibodies.


2022 ◽  
Vol 12 ◽  
Author(s):  
Suzanne Bezstarosti ◽  
Cynthia S. M. Kramer ◽  
Marry E. I. Franke-van Dijk ◽  
Manon Vergunst ◽  
Kim H. Bakker ◽  
...  

HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino acids on HLA molecules that require verification to confirm that they can be recognized by alloantibodies and are therefore clinically relevant. In this study, we isolated HLA-DQ specific memory B cells from immunized individuals by using biotinylated HLA-DQ monomers to generate 15 recombinant human HLA-DQ specific monoclonal antibodies (mAb) with six distinct specificities. Single antigen bead reactivity patterns were analyzed with HLA-EMMA to identify amino acids that were uniquely shared by the reactive HLA alleles to define functional epitopes which were mapped to known eplets. The HLA-DQB1*03:01-specific mAb LB_DQB0301_A and the HLA-DQB1*03-specific mAb LB_DQB0303_C supported the antibody-verification of eplets 45EV and 55PP respectively, while mAbs LB_DQB0402_A and LB_DQB0602_B verified eplet 55R on HLA-DQB1*04/05/06. For three mAbs, multiple uniquely shared amino acid configurations were identified, warranting further studies to define the inducing functional epitope and corresponding eplet. Our unique set of HLA-DQ specific mAbs will be further expanded and will facilitate the in-depth analysis of HLA-DQ epitopes, which is relevant for further studies of HLA-DQ alloantibody pathogenicity in transplantation.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Lisanne de Vor ◽  
Bruce van Dijk ◽  
Kok van Kessel ◽  
Jeffrey S Kavanaugh ◽  
Carla de Haas ◽  
...  

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.


Theranostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 1-17
Author(s):  
Kuan-Ying A. Huang ◽  
Daming Zhou ◽  
Tiong Kit Tan ◽  
Charles Chen ◽  
Helen M. E. Duyvesteyn ◽  
...  

2021 ◽  
Author(s):  
Kang Wang ◽  
Zijing Jia ◽  
Linlin Bao ◽  
Lei Wang ◽  
Lei Cao ◽  
...  

Omicron, the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising unprecedented concerns about the effectiveness of antibody therapies and vaccines. We examined whether sera from individuals who received two or three doses of inactivated vaccine, could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2/60) and 95% (57/60) for 2- and 3-dose vaccinees, respectively. For three-dose recipients, the geometric mean neutralization antibody titer (GMT) of Omicron was 15, 16.5-fold lower than that of the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in 3-dose vaccinees, half of which recognize the receptor binding domain (RBD) and show that a subset of them (24/163) neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron, potently. Therapeutic treatments with representative broadly neutralizing mAbs individually or antibody cocktails were highly protective against SARS-CoV-2 Beta infection in mice. Atomic structures of the Omicron S in complex with three types of all five VOC-reactive antibodies defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to one major class of antibodies bound at the right shoulder of RBD through altering local conformation at the binding interface. Our results rationalize the use of 3-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are a rational target for a universal sarbecovirus vaccine.


2021 ◽  
Author(s):  
Prashant Ranjan ◽  
Neha ◽  
Chandra Devi ◽  
Kaviyapriya Arulmozhi Devar ◽  
Parimal Das

The newly discovered COVID variant B.1.1.529 in Botswana has more than 30 mutations in spike and many other in non-spike proteins, far more than any other SARS-CoV-2 variant accepted as a variant of concern by the WHO and officially named Omicron, and has sparked concern among scientists and the general public. Our findings provide insights into structural modification caused by the mutations in the Omicrons receptor-binding domain and look into the effects on interaction with the hosts neutralising antibodies CR3022, B38, CB6, P2B-2F6, and REGN, as well as ACE2R using an in silico approach. We have employed secondary structure prediction, structural superimposition, protein disorderness, molecular docking, and MD simulation to investigate host-pathogen interactions, immune evasion, and transmissibility caused by mutations in the RBD region of the spike protein of the Omicron variant and compared it to the Delta variants (AY.1, AY.2, & AY.3) and wild type. Computational analysis revealed that the Omicron variant has a higher binding affinity for the human ACE2 receptor than the wild and Delta (AY.1 and AY.2 strains), but lower than the Delta AY.3 strain. MD simulation and docking analysis suggest that the omicron and Delta AY.3 were found to have relatively unstable and compact RBD structures and hampered interactions with antibodies more than wild and Delta (AY.1 and AY.2), which may lead to relatively more pathogenicity and antibody escape. In addition, we observed lower binding affinity of Omicron for human monoclonal antibodies (CR3022, B38, CB6, and P2B2F6) when compared to wild and Delta (AY.1 & AY.2). However, the binding affinity of Omicron RBD variants for CR3022, B38, and P2B2F6 antibodies is lower as compared to Delta AY.3, which might promote immune evasion and reinfection and needs further experimental investigation.


mBio ◽  
2021 ◽  
Author(s):  
Siriruk Changrob ◽  
Yanbin Fu ◽  
Jenna J. Guthmiller ◽  
Peter J. Halfmann ◽  
Lei Li ◽  
...  

We describe the binding and neutralization properties of a new set of human monoclonal antibodies derived from memory B cells of 10 coronavirus disease 2019 (COVID-19) convalescent donors in the first pandemic wave of prototype SARS-CoV-2. There were 12 antibodies targeting distinct epitopes on spike, including two sites on the RBD and one on the N-terminal domain (NTD), that displayed cross-neutralization of VOCs, for which distinct antibody targets could neutralize discrete variants.


Author(s):  
Rachelle Babb ◽  
Christopher R. Doyle ◽  
Liise-anne Pirofski

Despite the global success of vaccination with pneumococcal conjugate vaccines, serotype 3 (ST3) pneumococcus remains a leading cause of morbidity and mortality. In comparison to other vaccine-included serotypes, the ST3 pneumococcal capsular polysaccharide (PPS3) induces a weaker opsonophagocytic response, which is considered a correlate of vaccine efficacy.


Antibodies ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 45
Author(s):  
Tal Noy-Porat ◽  
Avishay Edri ◽  
Ron Alcalay ◽  
Efi Makdasi ◽  
David Gur ◽  
...  

The use of passively-administered neutralizing antibodies is a promising approach for the prevention and treatment of SARS-CoV-2 infection. Antibody-mediated protection may involve immune system recruitment through Fc-dependent activation of effector cells and the complement system. However, the role of Fc-mediated functions in the efficacious in-vivo neutralization of SARS-CoV-2 is not yet clear, and it is of high importance to delineate the role this process plays in antibody-mediated protection. Toward this aim, we have chosen two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, MD65 and BLN1 that target distinct domains of the spike (RBD and NTD, respectively). The Fc of these antibodies was engineered to include the triple mutation N297G/S298G/T299A that eliminates glycosylation and the binding to FcγR and to the complement system activator C1q. As expected, the virus neutralization activity (in-vitro) of the engineered antibodies was retained. To study the role of Fc-mediated functions, the protective activity of these antibodies was tested against lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice, when treatment was initiated either before or two days post-exposure. Antibody treatment with both Fc-variants similarly rescued the mice from death reduced viral load and prevented signs of morbidity. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in MD65 and BLN1 antibody-mediated protection, which should aid in the future design of effective antibody-based therapies.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2081-2081
Author(s):  
Szumam Liu ◽  
Mohammad Abdelgawwad ◽  
Shanrun Liu ◽  
X. Long Zheng

Abstract Introduction. Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. However, the structural feature, binding epitope, and the mechanism of action of these autoantibodies in patients with acute iTTP are not fully understood. Methods. To further understand the pathogenesis of iTTP, single B cell immunoglobulin (Ig) sequencing using 10xChromium in 4 patients experiencing an acute episode of iTTP was performed; the expression and preliminary functional characterizations of selected clones were also carried out. Results. Approximately 2,631 viable and fluoresceinated ADAMTS13 labeled B cells (e.g., 7AAD -CD19 +CD20 +ADAMTS13 +) were sorted out from peripheral blood mononuclear cells of four patients with acute iTTP. These enriched ADAMTS13 antibody-producing B cells were then used for single cell analysis using 10xGenomics 5'-VDJ kit following the manufacturer's instruction. The single-cell gene expression libraries and VDJ libraries were constructed and sequenced by Hiseq at 20,000 reads/cell for gene expression and 5,000 reads/cell for VDJ sequences. Sequencing FASTQ files were mapped and counted by running through the Cell Ranger pipeline, and the final data were then further analyzed by the Loupe browser. We showed for the first time that the most frequent VJ combinations in the anti-ADAMTS13 IgG were: IGHV4-39:ILGJ4, IGHV3-48:ILGJ4, IGLV1-44:ILGLJ2, GLV5-45:ILGLJ3, IGLV2-14:ILGJ2, and IGLV3-21:ILGJ3 as shown in Figure 1. Of the top ten clones, the most frequently observed CDR3 (complementarity-determining region-3) sequences of these antibodies were CARDQLGISETQGSDLW on the heavy chain and CVIWHNSAWVF on the light chain as shown in Figure 2 and Table 1. The variable region sequences from the heavy and the light chains of Ig molecules were cloned into a human IgHG1 and a human IgL vector, respectively, which was then cotransfected in HEK293 cells. Western blotting, ELISA, immunoprecipitation, and functional assays were used to determine the expression and the function of human monoclonal IgG antibodies. Our preliminary results demonstrated the human monoclonal IgG antibodies bound and/or inhibited plasma ADAMTS13 activity. Conclusions. We conclude that there is clonal expansion of ADAMTS13 antibody producing B cells in acute iTTP and the cloned human monoclonal antibodies using the single B cell sequencing approach are functional. Our ongoing analysis on the structural and functional relationship of a large number of isolated human monoclonal antibodies may shed new light on the pathogenesis of iTTP. These antibodies may be useful to explore structural elements required for allosteric regulation of ADAMTS13 activity. Figure 1 Figure 1. Disclosures Zheng: AJMC: Honoraria; Clotsolution: Other: Co-founder; Takeda: Consultancy, Honoraria; Sanofi-Genzyme: Honoraria, Speakers Bureau; Alexion: Speakers Bureau.


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