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Antibody

a technology of antifungal agents and antibodies, applied in the field of antifungal antibodies, can solve the problems of not allowing the detection of ia caused, compromising the ability to select the most appropriate antifungal agent,

Inactive Publication Date: 2012-03-15
UNIV OF EXETER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0044]The term “chimeric” refers to antibodies in which the whole of the variable regions of a mouse or rat antibody are expressed along with human constant regions. This provides the antibody with human effector functions and also reduces immunogenicity (HAMA) caused by the murine Fc region.
[0055]The invention provides antibodies that bind to Aspergillus. It is further envisaged that one skilled in the art could create more antibodies by altering the VH and / or VL sequence(s) provided. Such antibodies may be derived by a skilled person using techniques known in the art and are also encompassed by the invention. For example, modifications such as amino acid substitutions, deletions, or additions can be introduced into any part of the antibody, providing functionality remains. Changes may be introduced into the framework regions, especially to, for example improve the stability of the antibody. Changes may also be introduced into the CDRs to alter the antibody's affinity for the epitope. The affinity of an antibody for the epitope may be tested using standard techniques known in the art.

Problems solved by technology

Issues with galactomannan testing.
Issues with galactomannan testing.
Cyclophosphamide induces false-positive results in detection of Aspergillus antigen in urine.
Issues with galactomannan testing.
Clin. Microbiol. Infect. 12:40-52), its lack of specificity means that it is unable to discriminate between Aspergillus species and other opportunistic pathogens, which compromises the ability to select the most appropriate antifungal agent.
In contrast, an ELISA used to detect the Afmp1p cell wall antigen of A. fumigatus in patient's sera provides a high degree of specificity but does not allow the detection of IA caused by other Aspergillus species (Woo, P. C. Y., C-M.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Fungal Culture

[0114]All fungi were cultured on Sabouraud agar (SA) under a 16 h fluorescent light regime.

[0115]Development of mAb, preparation of immunogen, and immunization regime. Mice were immunized with lyophilized mycelium (LM) of A. fumigatus AF293. Minimal medium (19 mM (NH4)2PO4, 0.5% (wt / vol) yeast extract, 7 mM sodium citrate, 2 mM MgSO4.7H2O, 0.5 mM CaCl2.2H2O and 50 mM glucose, adjusted to pH 5.5 with 1 N HCl) was sterilized by autoclaving at 121° C. for 15 min. Three-wk-old SA Petri dish cultures of the fungus were flooded with 20 ml dH2O and the conidia suspended by gentle agitation using an inoculation loop. Spore suspensions were filtered through Miracloth to remove mycelium and the filtrate containing conidia transferred to 1.5 ml micro-centrifuge tubes. The conidia were washed three times with dH2O by repeated vortexing and centrifugation at 12 000 g for 5 min and finally suspended in dH2O to give a concentration of 106 conidia / ml solution. Flasks containing 150 ml...

example 2

Summary

[0133]Lectin binding studies show that the antigen(s) bound by MAb JF5 is / are immunogenic N-linked mannoprotein(s) comprising terminal non-reducing mannose residues linked α1-3 and α1-6. Insensitivity of the antigen(s) in ELISA to mild alkaline hydrolysis (β-elimination) shows that the MAb does not bind to glycan structures O-linked through serine and threonine.

Methodology

[0134]Lectin binding studies. Antigen(s) were purified from Aspergillus fumigatus using the method described. Purified antigen solution was subjected to glycoprotein fractionation using a Qproteome Mannose Glycoprotein Kit (Catalog no. 37551; Qiagen Ltd., Crawley, UK) according to the manufacturer's instructions. The ConA, GNA, and LCH lectin spin columns in the kit allow specific enrichment of glycoproteins with mannose-rich glycan moieties. The three lectins each bind different subclasses of these moieties. ConA binds biantennary and triantennary complex type N-glycans; LCH binds biantennary and triantenna...

example 3

Detection of Invasive Pulmonary Aspergillosis by Lateral Flow Technology Compared to Galactomannan and (1→0)-β-D-Glucan

[0140]Early diagnosis of invasive aspergillosis is critical for the initiation of appropriate antifungal therapy and may improve outcomes in high-risk patients. The use of sensitive biomarkers, including the non-invasive assays for galactomannan and (1→3)-β-D-glucan, also reduces the use of unnecessary antifungal agents. Despite their advantages, the galactomannan and the (1→3)-β-D-glucan assays are confined to laboratories equipped for these tests or require samples be sent to reference laboratories. Lateral-flow technology incorporates immunochromatographic assays into simple devices for point-of-care diagnosis. When coupled to a monoclonal antibody specific to an extracellular glycoprotein of Aspergillus this technology is a sensitive and specific biomarker (Thornton, C. R. 2008. Development of an Immunochromatographic Lateral-Flow Device for Rapid Serodiagnosis ...

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Abstract

The invention relates to antibodies to Aspergillus species and to methods of producing those antibodies. The invention also relates to the use of such antibodies in identifying the presence of the Aspergillus species and to methods of treating an infection with the Aspergillus species.

Description

FIELD OF THE INVENTION[0001]This invention relates to a method of diagnosing a fungal infection, and to antibodies and related molecules for use in such a method.BACKGROUND[0002]The dramatic increase in opportunistic infections of humans caused by Aspergillus species over the last decade is associated with a rise in the numbers of solid-organ transplants and the use of aggressive cancer therapies and other immuno-modulating treatments (Brakhage, A. A., and K. Langfelder. 2002. Menacing mold: the molecular biology of Aspergillus fumigatus. Annu. Rev. Microbiol. 56:433-455; Latgé, J.-P. 1999. Aspergillus fumigatus and Aspergillosis. Clin. Microbiol. Rev. 12:310-350). The mortality due to invasive aspergillosis (IA) has increased by 357% over the last 25 years and IA has become one of the leading causes of death in immuno-compromised patients, with mortality rates ranging from 60 to 90% (McNeil, M. M., S. L. Nash, R. A. Hajjeh, M. A. Phelan, L. A. Conn, B. D. Plikaytis, and D. L. Warno...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/14C12P21/02C12N1/21G01N33/569A61P31/10C12N5/10C12N1/19C12N5/16C12N15/13
CPCC07K16/14C07K2317/56G01N2469/20G01N33/56961G01N2333/38C07K2317/565A61P31/10
Inventor THORNTON, CHRISTOPHER
Owner UNIV OF EXETER