scholarly journals A repertoire of monoclonal antibodies with human heavy chains from transgenic mice

1989 ◽  
Vol 86 (17) ◽  
pp. 6709-6713 ◽  
Author(s):  
M Brüggemann ◽  
H M Caskey ◽  
C Teale ◽  
H Waldmann ◽  
G T Williams ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Transgenic Mice ◽  
Germ Line ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Human Monoclonal Antibodies ◽  
Human Antibodies ◽  
Heavy Chains ◽  
Serum Titer ◽  
Nonlymphoid Tissue

The introduction of human immunoglobulin gene segments in their unrearranged configuration into the germ line of mice might allow the production of a repertoire of human antibodies. Such transgenic mice could be used for the production of human monoclonal antibodies against human antigens. To test the feasibility of this approach, mice were created that carry a human heavy-chain minilocus comprising unrearranged immunoglobulin variable, diversity, and joining elements linked to a human mu-chain gene. The gene segments of this minilocus are rearranged in a large proportion of cells in thymus and spleen but not in nonlymphoid tissue. Some 4% of the B lymphocytes synthesize human mu chains resulting in a serum titer of about 50 micrograms of transgenic IgM antibody per ml. Hybridomas were established from the transgenic mice that stably secreted several micrograms of antibodies containing human mu heavy chains per milliliter.

scholarly journals Immunoglobulin gene rearrangements in normal mouse B cells

1982 ◽  
Vol 2 (7) ◽  
pp. 829-836
Author(s):  
P Early ◽  
C Nottenburg ◽  
I Weissman ◽  
L Hood
Keyword(s):  
B Cells ◽  
Heavy Chain ◽  
Germ Line ◽  
Gene Segment ◽  
Immunoglobulin M ◽  
Chain Gene ◽  
Allelic Exclusion ◽  
Immunoglobulin Gene ◽  
Spleen Cells ◽  
Surface Immunoglobulin

We have analyzed the structure of rearranged mu heavy-chain genes obtained from the genomic DNA of normal BALB/c mouse spleen cells expressing surface immunoglobulin M. Examples were found of two types of nonproductive rearrangements, which may be responsible for allelic exclusion in normal B cells. In one of these rearrangements, a germ line D gene segment has joined to the JH4 gene segment but no V/D joining has occurred. We present evidence that D gene segments lie as a cluster between V and J gene segments in the germ line. A comparison of conserved sequences in V and D gene segments suggests that the D gene segments, which are found only in the heavy-chain gene family, may have evolved from V gene segments similar to the Vk family.

Altered repertoire of endogenous immunoglobulin gene expression in transgenic mice containing a rearranged Mu heavy chain gene

Cell ◽  
1986 ◽  
Vol 45 (2) ◽  
pp. 247-259 ◽  
Author(s):  
David Weaver ◽  
Moema H. Reis ◽  
Christopher Albanese ◽  
Frank Costantini ◽  
David Baltimore ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Heavy Chain ◽  
Chain Gene ◽  
Immunoglobulin Gene ◽  
Heavy Chain Gene

Human and primate monoclonal antibodies for in vivo therapy.

1988 ◽  
Vol 34 (9) ◽  
pp. 1681-1688 ◽  
Author(s):  
P H Ehrlich ◽  
Z A Moustafa ◽  
J C Justice ◽  
K E Harfeldt ◽  
I K Gadi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Western Blot ◽  
Protein A ◽  
Human Chromosomes ◽  
Human Monoclonal Antibodies ◽  
Western Blot Assay ◽  
Human Antibodies ◽  
Low Levels ◽  
High Concentrations

Abstract Human monoclonal antibodies, owing to their decreased immunogenicity, are expected to be an improvement over mouse monoclonal antibodies for in vivo therapy. Human and primate monoclonal antibodies are best produced with a human x mouse heteromyeloma. Several human chromosomes are stable in the human x (human x mouse) hybrids. Chimpanzee anti-digoxin monoclonal antibodies were prepared and characterized. Because they are structurally very similar to human antibodies, they should be well tolerated in humans. The anti-digoxin antibodies can be used for therapy of extreme overdoses or as an in vivo diagnostic tool for slight overdoses. Because the advantage of using human monoclonal antibodies is their lack of immunogenicity, preparation of the antibody must be scrupulous so as not to introduce extraneous immunogens. Analysis to ensure the purity of the preparation can be complicated by the presence of high concentrations of the antibody and the low levels of contamination that must be detected. We describe a Western blot assay for Protein A that is sensitive even in the presence of human IgG.

scholarly journals Feedback inhibition of immunoglobulin gene rearrangement by membrane mu, but not by secreted mu heavy chains.

1988 ◽  
Vol 168 (4) ◽  
pp. 1363-1381 ◽  
Author(s):  
J Manz ◽  
K Denis ◽  
O Witte ◽  
R Brinster ◽  
U Storb
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Lines ◽  
Gene Rearrangement ◽  
Feedback Inhibition ◽  
Allelic Exclusion ◽  
Immunoglobulin Gene ◽  
Heavy Chains

Previous work (6-10) has shown that allelic exclusion of Ig gene expression is controlled by functionally rearranged mu and kappa genes. This report deals with the comparison of membrane mu (micron) and secreted mu (microsecond) in promoting such feedback inhibition. Splenic B cell hybridomas were analyzed from transgenic mice harboring a rearranged kappa gene alone or in combination with either an intact rearranged mu gene or a truncated version of the mu gene. The intact mu gene is capable of producing both membrane and secreted forms of the protein, while the truncated version can only encode the secreted form. The role of the microsecond was also tested in pre-B cell lines. Analysis of the extent of endogenous Ig gene rearrangement revealed that (a) the production of micron together with kappa can terminate Ig gene rearrangement; (b) microsecond with kappa does not have this feedback effect; (c) microsecond may interfere with the effect of micron and kappa; and (d) the feedback shown here probably represents a complete shutoff of the specific recombinase by micron + kappa; the data do not address the question of mu alone affecting the accessibility of H genes for rearrangement.

The diversity of antigen-specific monoclonal antibodies from transgenic mice bearing human immunoglobulin gene miniloci

1994 ◽  
Vol 24 (11) ◽  
pp. 2672-2681 ◽  
Author(s):  
Simon D. Wagner ◽  
Andrei V. Popov ◽  
Sarah L. Davies ◽  
Jian Xian ◽  
Michael S. Neuberger ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Transgenic Mice ◽  
Human Immunoglobulin ◽  
Immunoglobulin Gene

scholarly journals Naturally acquired blocking human monoclonal antibodies to Plasmodium vivax reticulocyte binding protein 2b

2020 ◽  
Author(s):  
Li-Jin Chan ◽  
Anugraha Gandhirajan ◽  
Lenore L. Carias ◽  
Melanie H. Dietrich ◽  
Oscar Vadas ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Plasmodium Vivax ◽  
Papua New Guinea ◽  
Binding Protein ◽  
Human Monoclonal Antibodies ◽  
Human Antibodies ◽  
Human Transferrin Receptor ◽  
Transferrin Receptor 1 ◽  
Functional Inhibition ◽  
Structural Mechanisms

AbstractPlasmodium vivax preferentially invades reticulocytes and recognition of these cells is mediated by P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) binding to human Transferrin receptor 1 (TfR1) and Transferrin (Tf). Longitudinal cohort studies in Papua New Guinea, Thailand and Brazil show that PvRBP2b antibodies are correlated with protection against P. vivax infection and disease. Here, we isolated and characterized anti-PvRBP2b human monoclonal antibodies from two individuals in Cambodia with natural P. vivax infection. These antibodies bind with high affinities and map to different regions of PvRBP2b. Several human antibodies blocked PvRBP2b binding to reticulocytes and inhibited complex formation with human TfR1-Tf. We describe different structural mechanisms for functional inhibition, including either steric hindrance with TfR1-Tf or the reticulocyte membrane. These results show that naturally acquired human antibodies against PvRBP2b can inhibit its function which is important for P. vivax invasion.

scholarly journals Broadly inhibiting anti-neuraminidase monoclonal antibodies induced by trivalent influenza vaccine and H7N9 infection in humans

2019 ◽  
Author(s):  
Pramila Rijal ◽  
Bei Bei Wang ◽  
Tiong Kit Tan ◽  
Lisa Schimanski ◽  
Philipp Janesch ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Influenza Vaccine ◽  
Influenza Viruses ◽  
List Type ◽  
Human Monoclonal Antibodies ◽  
Human Antibodies ◽  
Trivalent Influenza Vaccine ◽  
H7n9 Infection ◽  
Group 2 ◽  
Group 1

AbstractThe majority of antibodies induced by influenza neuraminidase (NA), like those against hemagglutinin (HA), are relatively specific to viruses isolated within a limited time-window as seen in serological studies and the analysis of many murine monoclonal antibodies. We report three broadly reactive human monoclonal antibodies (mAbs) targeting N1 NA. Two were isolated from a young adult vaccinated with trivalent influenza vaccine (TIV), which inhibited N1 NA from viruses isolated from human over a period of a hundred years. The third antibody isolated from a child with acute mild H7N9 infection inhibited both group 1 N1 and group 2 N9 NAs. In addition, the antibodies cross-inhibited the N1 NAs of highly pathogenic avian H5N1 influenza viruses. These antibodies are protective in prophylaxis against seasonal H1N1 viruses in mice. This study demonstrates that human antibodies to N1 NA with exceptional cross-reactivity can be recalled by vaccination and highlights the importance of standardizing the NA antigen in seasonal vaccines to offer optimal protection.ImportanceAntibodies to the influenza NA can provide protection against influenza disease. Analysis of human antibodies to NA lags behind that for HA. We show that human monoclonal antibodies against NA induced by vaccination and infection can be very broadly reactive and able to inhibit a wide spectrum of N1 NAs between 1918 and 2018. This suggests that antibodies to NA may be a useful therapy, and that efficacy of influenza vaccines could be enhanced by ensuring appropriate content of NA antigen.Highlights of the paperAntibodies that inhibit influenza viruses with N1 neuraminidase (NA), with broad reactivity for viruses isolated between 1918-2018, can be isolated from human recipients of seasonal influenza vaccineAntibodies targeting N1 NA of human seasonal H1N1 viruses can cross-react with a variety of avian N1 neuraminidasesAcute H7N9 infection can recall memory B cells to N1 NA and elicit cross-reactive antibodies to the group 1 N1 and group 2 N9 NAsAntibodies to N1 NA with this broad reactivity protect against lethal virus challenge

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