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Human monoclonal antibodies against bacillus anthracis protective antigen

A technology of Bacillus anthracis and human monoclonal antibodies, applied in the fields of peptides, immunoglobulins, chemical instruments and methods, etc., can solve the problems of inability to provide protection and interference with the development of expansive immune responses

Inactive Publication Date: 2006-07-26
ER SQUIBB & SONS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, in real-world exposures, antibodies can interfere with the development of a sustaining immune response, resulting in no protection after discontinuation of dosing

Method used

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  • Human monoclonal antibodies against bacillus anthracis protective antigen
  • Human monoclonal antibodies against bacillus anthracis protective antigen
  • Human monoclonal antibodies against bacillus anthracis protective antigen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1: Preparation of transgenic animals fully expressing human antibodies

[0219] I. Generation of transgenic (Cmu-targeted) mice

[0220] Construction of CMD targeting vector

[0221] Plasmid pICEmu contains the EcoRI / XhoI fragment of the murine Ig heavy chain locus spanning the mu gene obtained from the Balb / C genomic lambda phage library (Marcu et al. Cell 22:187, 1980). This genomic fragment was subcloned into the XhoI / EcoRI site of plasmid pICEMI9H (Marsh et al., Gene 32, 481-485, 1984). The heavy chain sequence included in pICEmu extends from downstream of the EcoRI site 3' of the mu intron-containing enhancer to an XhoI site approximately 1 kb downstream of the last transmembrane exon of the mu gene; however, most of the mu conversion repeats The region has been deleted by passaging in E. coli.

[0222] The targeting vector was constructed as follows. The 1.3 kb HindIII / SmaI fragment was excised from pICEmu and subcloned into HindIII / SmaI digested pBlue...

Embodiment 2

[0236] Example 2: Production of fully human antibodies against anthrax protective antigens

[0237] Human monoclonal antibodies against the anthrax protective antigen were raised in transgenic mice generated as described above as described below.

[0238] Production of human anti-PA monoclonal antibody

[0239] The transgenic HuMAb Mouse(R) line HC2 / KCo7, which has four different genetic modifications, was used for immunization. These transgenic mice contain human immunoglobulin gene miniloci that encode unrearranged human heavy (μ and γ) and kappa light chain immunoglobulin sequences, as well as targets for inactivation of the endogenous μ and κ chain loci. fixed mutation. Thus, the mice exhibit no expression of mouse IgM or kappa, and undergo class switching and somatic mutation to produce high affinity human IgG kappa monoclonal antibodies in response to immunization introduced human heavy and light chain transgenes.

[0240] Mice were housed in filter cages and assessed...

Embodiment 3A

[0246] Example 3A: In Vitro Neutralization of Lethal Toxin by Anti-PA Human Monoclonal Antibody

[0247] TNA experiments were performed according to Little et al., 1990, supra. Briefly, the toxin-sensitive murine macrophage cell line J774A.1 was exposed to a mixture of PA and LF (10:1 ) in the presence or absence of different concentrations of anti-PA mAb. After 3 hours of incubation, macrophage viability was determined using a viability dye (MTT). The results (Figure 10) demonstrate the activity of human anti-PA antibodies in neutralizing lethal toxin in vitro. Table 2 below shows that maintaining 50% viability of macrophages in TNA (ED 50 ) The effective dose of antibody required.

[0248] Antibody

ED 50 (μg / mL)

5D5

0.035

2H4

0.060

5E8

0.015

2D5

5

[0249] To examine direct binding to anthrax protective antigen, ELISA plates were coated with PA83 or PA63. mAb samples were added at appropr...

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Abstract

Isolated human monoclonal antibodies that bind anthrax protective antigens are disclosed. Human antibodies can be produced in non-human transgenic animals, such as transgenic mice, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are derivatives of human antibodies (e.g., bispecific antibodies and immunoconjugates), pharmaceutical compositions containing human antibodies, non-human transgenic animals and hybridomas producing human antibodies, and therapeutic and diagnostic uses of human antibodies method.

Description

Background of the invention [0001] Anthrax (Bacillus anthracis) is primarily a disease of domesticated and wild animals, especially herbivores such as cattle, sheep, horses, mules, and goats. Although natural anthrax infection in humans is rare (approximately 1 in 100,000 risk of infection through contact with sick animals), it poses a very real risk from bioterrorism. The bacterium forms hard spores that are heat resistant and can survive for decades under natural conditions. Although cutaneous anthrax is easier to treat, inhalational anthrax usually results in sudden, catastrophic illness with a mortality rate of over 80% within 2-4 days. The disease spreads easily due to the stability of the spores, as evidenced by the five deaths that occurred in the United States in 2002. If anthrax spores were spread through terrorism, the event would likely go undetected until many people were hospitalized or died. Current treatments, including antibiotics and vaccines, cannot help t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00
Inventor T·克勒D·布兰塞特L·A·瓦伊塔尔I·洛维M·斯里尼瓦桑
Owner ER SQUIBB & SONS INC
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