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A method for inhibiting alternative pathway mediated disorders with anti-properdin antibodies that inhibit c5 interactions with properdin

A technology of alternate complement pathway and properdin, applied in the field of anti-properdin antibody agent, can solve the problem of not finding anti-properdin antibody and the like

Active Publication Date: 2013-04-24
NOVELMED THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Anti-properdin antibodies not previously found to bind C5 or C5b

Method used

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  • A method for inhibiting alternative pathway mediated disorders with anti-properdin antibodies that inhibit c5 interactions with properdin
  • A method for inhibiting alternative pathway mediated disorders with anti-properdin antibodies that inhibit c5 interactions with properdin
  • A method for inhibiting alternative pathway mediated disorders with anti-properdin antibodies that inhibit c5 interactions with properdin

Examples

Experimental program
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Effect test

preparation example Construction

[0107] Preparation of anti-properdin antibody

[0108] Preparation of anti-properdin antibodies can be accomplished by using intact properdin, a properdin polypeptide, and / or using an antigenic properdin epitope-loaded peptide (eg, a portion of a properdin polypeptide). Properdin peptides and polypeptides can be isolated for use in raising antibodies as native polypeptides, recombinant or synthetic peptides, and catalytically inactive recombinant polypeptides. This embodiment of the invention can provide anti-properdin antibodies obtained using transgenic mouse strains. Antigens for raising anti-properdin antibodies also include fusion polypeptides.

[0109] polyclonal antibody

[0110] Using well-known methods, polyclonal antibodies to properdin can be prepared by immunizing an animal with a properdin polypeptide, or an immunogenic portion thereof, to produce polyclonal antibodies. Polyclonal antibodies are typically raised in animals such as dogs, goats, chickens, rats, m...

Embodiment 1

[0168] Properdin-binding complement proteins C3b, C5 / C5b and C9

[0169] Properdin is known to bind C3b with high affinity. We demonstrate that properdin binds C5 / C5b and C9 with high affinity and provides minimal or no properdin binding to C6, C7 and C8. Both C3 and C5 exist as intact proteins, however upon substrate binding they are converted to C3b and C5b, respectively. To date there are no published reports demonstrating that properdin binds C5 and / or C5b. By inhibiting the binding of properdin to C5 / C5b, we demonstrated to block the activation of the alternative pathway. Human C3, C5, C6, C7, C8 and C9 were coated with 2.0 μg / 50 μl polystyrene microtiter plate per well in phosphate buffered saline (PBS) overnight at 4°C. After aspirating the protein solution, the wells were blocked with PBS containing 1% bovine serum albumin (BSA) for 2 hours at room temperature. Wells without complement protein coating served as a background control. Aliquots of properdin at variou...

Embodiment 2

[0171] Anti-properdin IgG and F(ab') 2 Inhibition of alternative pathway (AP)-dependent rabbit red blood cell (rRBC) lysis

[0172] This erythrocyte lysis assay is based on the formation of terminal complement complexes on the rRBC surface. Thus, rRBC cells are lysed. A progressive decrease in light scatter at 700 nm is a direct measure of erythrocyte lysis. Typically, rRBC in the presence of 5mM MgCl 2 gelatin-Verona buffer and incubated in normal human serum. Under these conditions, the surface of rRBCs elicited the activation of the alternative pathway in normal human serum. Alternative pathway activation leads to the formation of C5b-9 complexes on the surface of rRBCs. Agents that inhibit C5b-9 complex formation are expected to inhibit cell lysis. To evaluate the effect of anti-properdin antibodies and their fragments, various concentrations of IgG, F(ab') 2 Incubate with Fab and normal human serum (10% NHS) in AP buffer at 37°C with a fixed concentration of rabbit...

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Abstract

A method of inhibiting the alternative complement pathway activation in a subject mammal includes administering an amount of an antibody and / or fragment thereof that specifically binds to properdin and inhibit properdin binding to a complement protein, for example, C5, to inhibit the alternative complement pathway in the subject mammal.

Description

[0001] related application [0002] This application claims priority to US Provisional Application No. 61 / 309,705, filed March 2, 2010, the subject matter of which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to anti-properdin antibody agents that inhibit the binding of properdin to complement proteins such as C5 or C5b, and the use of these antibodies in the prophylactic and therapeutic settings of mammals to selectively inhibit alternative complement pathway function to prevent, Stop or reverse disease progression. Background technique [0004] The complement system is important for host defense against pathogens and is involved in the clearance of, for example, pathogens, bacterial cells, foreign antigens and tumor cells. Activation of the alternative complement pathway (AP) due to pathogenic inflammation and autoimmune diseases. Elevated levels of C3a, C5a and C5b-9 have been found to be associated with sev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7105A61K39/395A61K9/127A61K9/48A61K9/16A61P25/00
CPCC07K16/18C07K2317/34C07K2317/54C07K2317/76A61P25/00
Inventor R·班萨尔
Owner NOVELMED THERAPEUTICS
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