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Berlin Brandenburg

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  • 1
    Language: English
    In: Seminars in thrombosis and hemostasis, 2000, Vol.Volume 26(Number 02), pp.143-150
    Description: ABSTRACT Hemophilia A is a X-linked bleeding disorder that is caused by the functional absence of blood coagulation factor VIII. The bleeding tendency in hemophilia A patients can be corrected by the administration of plasma-derived or recombinant factor VIII concentrates. A serious complication in hemophilia care is the development of factor VIII neutralizing antibodies (inhibitors) that arise as a consequence of factor VIII replacement therapy. The majority of factor VIII inhibitors are directed toward epitopes located within the A2, A3, and C2 domains of factor VIII. In this article, we summarize current knowledge on the epitope specificity of factor VIII inhibitors. In addition, we will discuss recent information on the molecular characteristics of human anti-factor VIII antibodies generated by phage display technology.
    Keywords: Factor Viii ; Hemophilia ; Factor Viii Inhibitors ; Phage Display ; Scfv
    ISSN: 0094-6176
    E-ISSN: 1098-9064
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  • 2
    Language: English
    In: Cancer Research, 08/01/2015, Vol.75(15 Supplement), pp.634-634
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: English
    In: mAbs, 01 March 2014, Vol.6(2), pp.392-402
    Description: The human epidermal growth factor receptor (HER)2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody-drug conjugates (ADC) as has been clinically validated by ado-trastuzumab emtansine (Kadcyla TM ). While...
    Keywords: Her2 ; Pseudomonas Exotoxin A ; Antibody-Drug Conjugate ; Cancer ; Monoclonal Antibody ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1942-0862
    E-ISSN: 1942-0870
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  • 4
    Language: English
    In: The Lancet, June 26, 2004, Vol.364(9427), p.2139
    Keywords: Severe Acute Respiratory Syndrome -- Research ; Coronavirus Infections -- Research ; Monoclonal Antibodies -- Research
    ISSN: 0140-6736
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  • 5
    Language: English
    In: PLoS ONE, 2008, Vol.3(12), p.e3942
    Description: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. ; Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. ; The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens.
    Keywords: Research Article ; Biotechnology ; Immunology -- Immunity To Infections ; Immunology -- Innate Immunity ; Microbiology -- Innate Immunity ; Virology -- Antivirals, Including Modes Of Action And Resistance ; Virology -- New Therapies, Including Antivirals And Immunotherapy ; Infectious Diseases -- Respiratory Infections ; Infectious Diseases -- Viral Infections ; Respiratory Medicine -- Respiratory Infections
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: The Lancet, 26 June 2004, Vol.363(9427), pp.2139-2141
    Description: SARS coronavirus continues to cause sporadic cases of severe acute respiratory syndrome (SARS) in China. No active or passive immunoprophylaxis for disease induced by SARS coronavirus is available. We investigated prophylaxis of SARS coronavirus infection with a neutralising human monoclonal antibody in ferrets, which can be readily infected with the virus. Prophylactic administration of the monoclonal antibody at 10 mg/kg reduced replication of SARS coronavirus in the lungs of infected ferrets by 3·3 logs (95% Cl 2·6–4·0 logs; p〈0·001), completely prevented the development of SARS coronavirus-induced macroscopic lung pathology (p=0·013), and abolished shedding of virus in pharyngeal secretions. The data generated in this animal model show that administration of a human monoclonal antibody might offer a feasible and effective prophylaxis for the control of human SARS coronavirus infection.
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 7
    In: The Journal of Virology, 2005, Vol. 79(3), p.1635
    Description: Human monoclonal antibodies (MAbs) were selected from semisynthetic antibody phage display libraries by using whole irradiated severe acute respiratory syndrome (SARS) coronavirus (CoV) virions as target. We identified eight human MAbs binding to virus and infected cells, six of which could be mapped to two SARS-CoV structural proteins: the nucleocapsid (N) and spike (S) proteins. Two MAbs reacted with N protein. One of the N protein MAbs recognized a linear epitope conserved between all published human and animal SARS-CoV isolates, and the other bound to a nonlinear N epitope. These two N MAbs did not compete for binding to SARS-CoV. Four MAbs reacted with the S glycoprotein, and three of these MAbs neutralized SARS-CoV in vitro. All three neutralizing anti-S MAbs bound a recombinant S1 fragment comprising residues 318 to 510, a region previously identified as the SARS-CoV S receptor binding domain; the nonneutralizing MAb did not. Two strongly neutralizing anti-S1 MAbs blocked the binding of a recombinant S fragment (residues 1 to 565) to SARS-CoV-susceptible Vero cells completely, whereas a poorly neutralizing S1 MAb blocked binding only partially. The MAb ability to block S1-receptor binding and the level of neutralization of the two strongly neutralizing S1 MAbs correlated with the binding affinity to the S1 domain. Finally, epitope mapping, using recombinant S fragments (residues 318 to 510) containing naturally occurring mutations, revealed the importance of residue N479 for the binding of the most potent neutralizing MAb, CR3014. The complete set of SARS-CoV MAbs described here may be useful for diagnosis, chemoprophylaxis, and therapy of SARS-CoV infection and disease.
    Keywords: Sars Coronavirus ; Sars Coronavirus ; Monoclonal Antibodies ; Severe Acute Respiratory Syndrome ; N Protein ; Nucleocapsids ; Phage Display ; Virions ; Vero Cells ; Epitope Mapping ; Infection ; Structural Proteins ; Glycoproteins ; Mutation ; Monoclonal Antibodies ; Severe Acute Respiratory Syndrome ; ^An Protein ; Nucleocapsids ; Phage Display ; Virions ; Vero Cells ; Epitope Mapping ; Infection ; Structural Proteins ; Glycoproteins ; Mutation ; Immunological Techniques & Reagents ; Monoclonal Antibodies, Hybridoma, Antigens;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 8
    Language: English
    In: Blood, 2002, Vol.99(8), pp.2828-2834
    Description: Most plasmas from patients with inhibitors contain antibodies that are reactive with the C2 domain of factor VIII. Previously, we have shown that the variable heavy chain (V(H)) regions of antibodies to the C2 domain are encoded by the closely related germline gene segments DP-10, DP-14, and DP-88, which all belong to the V(H)1 gene family. Here, we report on the isolation and characterization of additional anti-C2 antibodies that are derived from V(H) gene segments DP-88 and DP-5. Competition experiments using murine monoclonal antibodies CLB-CAg 117 and ESH4 demonstrated that antibodies derived from DP-5 and DP-88 bound to different sites within the C2 domain. Epitope mapping studies using a series of factor VIII/factor V hybrids revealed that residues 2223 to 2332 of factor VIII are required for binding of the DP-10-, DP-14-, and DP-88-encoded antibodies. In contrast, binding of the DP-5-encoded antibodies required residues in both the amino- and carboxy-terminus of the C2 domain. Inspection of the reactivity of the antibodies with a series of human/porcine hybrids yielded similar data. Binding of antibodies derived from germline gene segments DP-10, DP-14, and DP-88 was unaffected by replacement of residues 2181 to 2243 of human factor VIII for the porcine sequence, whereas binding of the DP-5-encoded antibodies was abrogated by this replacement. Together these data indicate that antibodies assembled from V(H) gene segments DP-5 and the closely related germline gene segments DP-10, DP-14, and DP-88 target 2 distinct antigenic sites in the C2 domain of factor VIII
    Keywords: Factor VIII -- Immunology ; Genes, Immunoglobulin -- Immunology ; Immunoglobulin Heavy Chains -- Genetics ; Immunoglobulin Variable Region -- Genetics ; Isoantibodies -- Immunology;
    ISSN: 0006-4971
    ISSN: 1528-0020
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  • 9
    In: British Journal of Haematology, November 2002, Vol.119(2), pp.393-396
    Description: We characterized anti‐factor VIII antibodies in a mild haemophilia A patient with an Arg→Cys mutation in the A2 domain, using V gene phage‐display technology. All isolated single‐chain variable‐domain antibody fragments were directed against residues Arg‐Ile, a binding site for factor VIII inhibitors in the A2 domain. After a further period of replacement therapy, a transient rise in inhibitor titre was observed. These antibodies were directed against the A2 domain. Activation of a pre‐existing pool of B cells, which express antibodies against residues Arg‐Ile, could explain the rapid anamnestic response.
    Keywords: Factor Viii Inhibitors ; Haemophilia A ; Phage Display ; B Lymphocyte ; Immunoglobulin Repertoire
    ISSN: 0007-1048
    E-ISSN: 1365-2141
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  • 10
    Language: English
    In: PLoS Medicine, 2006, Vol.3(7), p.e237
    Description: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. ; Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. ; The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection. ; Late in 2002, severe acute respiratory syndrome (SARS) emerged in the Guangdong province of China. In February 2003, an infected doctor from the province carried this new viral threat to human health to Hong Kong. Here, people staying in the same hotel caught the disease and took it to other countries. SARS was on the move, hitching lifts with international travellers. Because the virus responsible for SARS—SARS-CoV—spread by close person-to-person contact and killed 10% of the people it infected, health experts feared a world-wide epidemic. This was avoided by the World Health Organization issuing a global alert and warning against unnecessary travel to affected areas and by public-health officials isolating patients and their close contacts. By July 2003, the first SARS epidemic was over. 8,098 people had been infected; 774 people had died. Since then, sporadic cases of SARS have been contained locally. ; The first epidemic of SARS was caused by an animal virus that became adapted to spread between people. There is no reason this process won't be repeated. If it is, stringent quarantine measures could again prevent a global epidemic, but at considerable economic cost. What is needed is a way to prevent SARS developing in healthy people who have been exposed to SARS-CoV and to treat sick people so that they are less infectious and can fight the virus. In this study, researchers have been investigating “passive immunization” as a way to limit SARS epidemics. In passive immunization, short-term protection against illness is achieved by injecting antibodies—proteins that recognize specific molecules (called antigens) on foreign organisms such as bacteria and viruses and prevent those organisms from causing disease. Antibodies for passive immunization can be isolated from blood taken from people who have had SARS, or they can be manufactured as so-called “human monoclonal antibodies” in a laboratory. One of these human monoclonal antibodies—CR3014—had been previously made and shown to prevent lung damage in ferrets infected with SARS-CoV and to stop the infected animals from infecting others. But for effective disease prevention in people, a single monoclonal antibody might not be enough. There are strains of SARS-CoV that CR3014 does not recognize and therefore cannot act against. Also, the virus can alter the antigen recognized by CR3014 when it is grown at a low antibody concentration, producing so-called escape variants; if this happens CR3014 can no longer prevent these escape variants from killing human cells. ; The researchers tested how well a combination of two monoclonal antibodies controlled SARS-CoV killing of human cells. First, they showed that CR3014 escape variants all had the same small change in a part of the virus surface that interacts with human cells. CR3014 blocked this interaction in the parent SARS-CoV strain but not in the escape variants. They then made a new monoclonal antibody—CR3022—that prevented both the parent SARS-CoV stain and the CR3014 escape viruses from killing human cells. The two antibodies bound to neighboring parts of the virus surface, and both of them could bind at the same time. CR3022 also bound to surfaces of SARS-CoV strains to which CR3014 does not bind. And when they tried, the researchers could not generate any viral escape variants to which CR3022 was unable to bind. Finally, the effect of the two antibodies together on inhibition of SARS-CoV killing of human cells was more than the sum of their individual effects. ; A combination of two (or more) human monoclonal antibodies that recognize different parts of the SARS-CoV surface that interacts with human cells might be a good way to immunize people passively against SARS-CoV. It might minimize the possibility of escape variants arising, broaden the range of virus strains against which protection is provided, and reduce the amount of antibody needed for effective protection. Before the approach is tried in people, it will have to be tested in animals—results from experiments done on human cells in dishes are not always replicated in whole animals or people. If the approach passes further tests, the hope is that passive immunization of people with SARS and their close contacts might reduce disease severity in infected people and reduce viral spread as effectively as dramatic quarantine measures. ; Please access these websites via the online version of this summary at . ; • Medline Plus pages on . ; • US Centers for Disease Control and Prevention information on . ; • US National Institute of Allergy and Infectious Diseases factsheet about . ; • Wikipedia page on and (note: Wikipedia is a free online encyclopedia that anyone can edit). ; Two human monoclonal antibodies that bind to different parts of the viral glycoprotein spike show synergistic effects in virus neutralization and suppress the emergence of resistant virus in vitro.
    Keywords: Research Article ; Biochemistry -- Drug Discovery ; Respiratory Medicine ; Drugs And Adverse Drug Reactions ; Infectious Diseases ; Immunology And Allergy ; Respiratory Medicine
    ISSN: 1549-1277
    E-ISSN: 1549-1676
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