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Cross-Reactive Human IgM-Derived Monoclonal Antibodies that Bind to HIV-1 Envelope Glycoproteins  [PDF]
Weizao Chen,Zhongyu Zhu,Huaxin Liao,Gerald V. Quinnan,Christopher C. Broder,Barton F. Haynes,Dimiter S. Dimitrov
Viruses , 2010, DOI: 10.3390/v2020547
Abstract: Elicitation of antibodies with potent and broad neutralizing activity against HIV by immunization remains a challenge. Several monoclonal antibodies (mAbs) isolated from humans with HIV-1 infection exhibit such activity but vaccine immunogens based on structures containing their epitopes have not been successful for their elicitation. All known broadly neutralizing mAbs (bnmAbs) are immunoglobulin (Ig) Gs (IgGs) and highly somatically hypermutated which could impede their elicitation. Ig Ms (IgMs) are on average significantly less divergent from germline antibodies and are relevant for the development of vaccine immunogens but are underexplored compared to IgGs. Here we describe the identification and characterization of several human IgM-derived mAbs against HIV-1 which were selected from a large phage-displayed naive human antibody library constructed from blood, lymph nodes and spleens of 59 healthy donors. These antibodies bound with high affinity to recombinant envelope glycoproteins (gp140s, Envs) of HIV-1 isolates from different clades. They enhanced or did not neutralize infection by some of the HIV-1 primary isolates using CCR5 as a coreceptor but neutralized all CXCR4 isolates tested although weakly. One of these antibodies with relatively low degree of somatic hypermutation was more extensively characterized. It bound to a highly conserved region partially overlapping with the coreceptor binding site and close to but not overlapping with the CD4 binding site. These results suggest the existence of conserved structures that could direct the immune response to non-neutralizing or even enhancing antibodies which may represent a strategy used by the virus to escape neutralizing immune responses. Further studies will show whether such a strategy plays a role in HIV infection of humans, how important that role could be, and what the mechanisms of infection enhancement are. The newly identified mAbs could be used as reagents to further characterize conserved non-neutralizing, weakly neutralizing or enhancing epitopes and modify or remove them from candidate vaccine immunogens.
Toward the Assessment of Food Toxicity for Celiac Patients: Characterization of Monoclonal Antibodies to a Main Immunogenic Gluten Peptide  [PDF]
Belén Morón, Michael T. Bethune, Isabel Comino, Hamid Manyani, Marina Ferragud, Manuel Carlos López, ángel Cebolla, Chaitan Khosla, Carolina Sousa
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002294
Abstract: Background and Aims Celiac disease is a permanent intolerance to gluten prolamins from wheat, barley, rye and, in some patients, oats. Partially digested gluten peptides produced in the digestive tract cause inflammation of the small intestine. High throughput, immune-based assays using monoclonal antibodies specific for these immunotoxic peptides would facilitate their detection in food and enable monitoring of their enzymatic detoxification. Two monoclonal antibodies, G12 and A1, were developed against a highly immunotoxic 33-mer peptide. The potential of each antibody for quantifying food toxicity for celiac patients was studied. Methods Epitope preferences of G12 and A1 antibodies were determined by ELISA with gluten-derived peptide variants of recombinant, synthetic or enzymatic origin. Results The recognition sequences of G12 and A1 antibodies were hexameric and heptameric epitopes, respectively. Although G12 affinity for the 33-mer was superior to A1, the sensitivity for gluten detection was higher for A1. This observation correlated to the higher number of A1 epitopes found in prolamins than G12 epitopes. Activation of T cell from gluten digested by glutenases decreased equivalently to the detection of intact peptides by A1 antibody. Peptide recognition of A1 included gliadin peptides involved in the both the adaptive and innate immunological response in celiac disease. Conclusions The sensitivity and epitope preferences of the A1 antibody resulted to be useful to detect gluten relevant peptides to infer the potential toxicity of food for celiac patients as well as to monitor peptide modifications by transglutaminase 2 or glutenases.
Phage Display-based Strategies for Cloning and Optimization of Monoclonal Antibodies Directed against Human Pathogens  [PDF]
Nicola Clementi,Nicasio Mancini,Laura Solforosi,Matteo Castelli,Massimo Clementi,Roberto Burioni
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13078273
Abstract: In the last two decades, several phage display-selected monoclonal antibodies (mAbs) have been described in the literature and a few of them have managed to reach the clinics. Among these, the anti-respiratory syncytial virus (RSV) Palivizumab, a phage-display optimized mAb, is the only marketed mAb directed against microbial pathogens. Palivizumab is a clear example of the importance of choosing the most appropriate strategy when selecting or optimizing an anti-infectious mAb. From this perspective, the extreme versatility of phage-display technology makes it a useful tool when setting up different strategies for the selection of mAbs directed against human pathogens, especially when their possible clinical use is considered. In this paper, we review the principal phage display strategies used to select anti-infectious mAbs, with particular attention focused on those used against hypervariable pathogens, such as HCV and influenza viruses.
Prophylactic and therapeutic activity of fully human monoclonal antibodies directed against Influenza A M2 protein
Roger R Beerli, Monika Bauer, Nicole Schmitz, Regula B Buser, Myriam Gwerder, Simone Muntwiler, Wolfgang A Renner, Philippe Saudan, Martin F Bachmann
Virology Journal , 2009, DOI: 10.1186/1743-422x-6-224
Abstract: Influenza A virus still is a major cause of disease in humans, accounting for three to five million cases of severe illness and 250,000 - 500,000 deaths each year [1]. Efficient influenza A vaccines are available, which induce antibodies predominantly against the two major components of the virus membrane, hemagglutinin (HA) and neuramidase (NA). Protection is mediated primarily by neutralizing antibodies against HA [2,3]. Since HA undergoes continuous change due to mutations (antigenic drift), new antigenic variants of influenza A arise every year requiring constant update of the vaccines. Effective vaccination is further complicated by the occasional reassortment of the segmented viral genome leading to the replacement of HA or NA from one subtype by another subtype, a processs called antigenic shift [4]. Passive immunization with monoclonal antibodies (mAbs) targeting HA is very efficient [5-7], however, suffers the same disadvantages as the current vaccines due to antigenic shift and drift.An ideal target for active and passive immunization strategies would therefore be a conserved viral protein. The matrix protein 2 (M2) fits the bill and has received considerable attention as a potential target against influenza infection over the past decades [8-23]. M2 is a tetrameric ion channel [24-26] which is involved in virus uncoating in the endosome and in virus maturation in the trans-Golgi network [27-29]. Its 23 amino acid extracellular domain has remained remarkably conserved in human influenza A virus isolates over the last hundred years [30], at least in part due to the fact that the M2 protein is co-transcribed with the matrix protein 1 (M1) [31,32]. Whereas M2 is abundantly expressed on infected cells, only very few M2 molecules are present in Influenza A virus membranes [23,26]. In accordance with this, current seasonal influenza vaccines do not induce a significant humoral resonse against M2, and M2 specific antibodies (administered intravenously or induced
Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia
Séverine Loisel, Pierre-Alain André, Josee Golay, Franz Buchegger, Jean Kadouche, Martine Cérutti, Luca Bologna, Marek Kosinski, David Viertl, Angelika Delaloye, Christian Berthou, Jean-Pierre Mach, Laurence Boumsell
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-42
Abstract: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5.Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.Monoclonal antibodies (mAb) have become an integral part in different treatments of lymphomas and leukaemias either as monotherapy or combined with chemotherapy and other antibodies. MAbs can be used in the form of unmodified antibodies or conjugated to radioactive elements or toxins. Anti-CD20 rituximab (Mabthera, Rituxan) has been extensively used and approved for the treatment of patients with various types of B-cell Non-Hodgkin Lymphoma (NHL). For the t
Monoclonal antibodies as diagnostics; an appraisal  [cached]
Siddiqui M
Indian Journal of Pharmaceutical Sciences , 2010,
Abstract: Ever since the development of Hybridoma Technology in 1975 by Kohler and Milstein, our vision for antibodies as tools for research for prevention, detection and treatment of diseases, vaccine production, antigenic characterization of pathogens and in the study of genetic regulation of immune responses and disease susceptibility has been revolutionized. The monoclonal antibodies being directed against single epitopes are homogeneous, highly specific and can be produced in unlimited quantities. In animal disease diagnosis, they are very useful for identification and antigenic characterization of pathogens. Monoclonal antibodies have tremendous applications in the field of diagnostics, therapeutics and targeted drug delivery systems, not only for infectious diseases caused by bacteria, viruses and protozoa but also for cancer, metabolic and hormonal disorders. They are also used in the diagnosis of lymphoid and myeloid malignancies, tissue typing, enzyme linked immunosorbent assay, radio immunoassay, serotyping of microorganisms, immunological intervention with passive antibody, antiidiotype inhibition, or magic bullet therapy with cytotoxic agents coupled with anti mouse specific antibody. Recombinant deoxyribonucleic acid technology through genetic engineering has successfully led to the possibility of reconstruction of monoclonal antibodies viz. chimeric antibodies, humanized antibodies and complementarily determining region grafted antibodies and their enormous therapeutic use.
Antigen-Specific Monoclonal Antibodies Isolated from B Cells Expressing Constitutively Active STAT5  [PDF]
Ferenc A. Scheeren,Caroline M. M. van Geelen,Etsuko Yasuda,Hergen Spits,Tim Beaumont
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017189
Abstract: Fully human monoclonal antibodies directed against specific pathogens have a high therapeutic potential, but are difficult to generate.
Effect of anti-glycosphingolipid monoclonal antibodies in pathogenic fungal growth and differentiation. Characterization of monoclonal antibody MEST-3 directed to Manpα1→3Manpα1→2IPC
Marcos S Toledo, Loriane Tagliari, Erika Suzuki, Claudinei M Silva, Anita H Straus, Helio K Takahashi
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-47
Abstract: In this paper, we describe a detailed characterization of an IgG2a monoclonal antibody (mAb), termed MEST-3, directed to the Paracoccidioides brasiliensis glycolipid antigen Pb-2 (Manpα1→3Manpα1→2IPC). mAb MEST-3 also recognizes GIPCs bearing the same structure in other fungi. Studies performed on fungal cultures clearly showed the strong inhibitory activity of MEST-3 on differentiation and colony formation of Paracoccidioides brasiliensis, Histoplasma capsulatum and Sporothrix schenckii. Similar inhibitory results were observed when these fungi where incubated with a different mAb, which recognizes GIPCs bearing terminal residues of β-D-galactofuranose linked to mannose (mAb MEST-1). On the other hand, mAb MEST-2 specifically directed to fungal glucosylceramide (GlcCer) was able to promote only a weak inhibition on fungal differentiation and colony formation.These results strongly suggest that mAbs directed to specific glycosphingolipids are able to interfere on fungal growth and differentiation. Thus, studies on surface distribution of GIPCs in yeast and mycelium forms of fungi may yield valuable information regarding the relevance of glycosphingolipids in processes of fungal growth, morphological transition and infectivity.Drouhet [1] described the existence of over 72,000 species of fungi widespread in nature, and more than 300 may be associated with human mycoses. In the last two decades, it was observed a dramatic raise in mortality of immunosupressed individuals associated with fungal infection. Although antifungal therapies have been successful and selective, the outbreaks of resistant strains, together with an increase on fungal tolerance levels to currently available antifungal, were described by several reports [1,2]. Therefore, a compelling search for novel antifungal therapies has been greatly stimulated. Studies carried out during the 1990s demonstrated that many species of fungi are vulnerable to inhibitors of enzymes of the sphingolipid biosynthesis
Generation of Monoclonal Antibodies against Highly Conserved Antigens  [PDF]
Hongzhe Zhou, Yunbo Wang, Wei Wang, Junying Jia, Yuan Li, Qiyu Wang, Yanfang Wu, Jie Tang
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006087
Abstract: Background Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is very crucial for the success of the drug development. However, due to immune tolerance, some proteins that are highly conserved between mice and humans are not very immunogenic in mice, making it difficult to generate antibodies using a conventional approach. Methodology/Principal Findings In this report, the impaired immune tolerance of NZB/W mice was exploited to generate monoclonal antibodies against highly conserved or self-antigens. Using two highly conserved human antigens (MIF and HMGB1) and one mouse self-antigen (TNF-alpha) as examples, we demonstrate here that multiple clones of high affinity, highly specific antibodies with desired biological activities can be generated, using the NZB/W mouse as the immunization host and a T cell-specific tag fused to a recombinant antigen to stimulate the immune system. Conclusions/Significance We developed an efficient and universal method for generating surrogate or therapeutic antibodies against “difficult antigens” to facilitate the development of therapeutic antibodies.
Preparation and characterization of monoclonal antibodies against adenylate kinase
Xide Wang,Junmei Zhou,Zhenquan Guo
Science China Life Sciences , 1997, DOI: 10.1007/BF02882685
Abstract: Six hybridoma cell lines that can continuously secrete monoclonal antibodies against adenylate kinase (AK) have been produced. The characteristics including the subclass and molecular weight of monoclonal antibodies manufactured by these strains are also determined. Further studies show that the two monoclonal antibodies McAb3D3 and McAb4D8 bind easily with AK absorbed on microtitration plates, with affinity constants of 8.4 × 108 M-1 and 9.6 × 108 M-1, while their interactions to AK in solution are much weaker, with affinity constants of 7.0 × 104 M-1 and 3.9×106 M-1, respectively. Thus, McAb3D3 and McAb4D8 react preferentially to the immobilized AKs. Since proteins are often partially denatured when absorbed on microtitration plates, it is suggested that both McAb3D3 and McAb4D8 are directed against non-native AK.
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