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Humanized and chimeric anti-factor c3 antibodies and uses thereof

A humanized and anti-factor technology, applied in the direction of antibodies, anti-animal/human immunoglobulins, anti-inflammatory agents, etc., can solve the problem of lack of specific targeting and inhibition for human use

Active Publication Date: 2014-12-17
NOVELMED THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite this, there is currently a complete lack of approved drugs for human use that specifically target and inhibit complement activation

Method used

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  • Humanized and chimeric anti-factor c3 antibodies and uses thereof
  • Humanized and chimeric anti-factor c3 antibodies and uses thereof
  • Humanized and chimeric anti-factor c3 antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] All reagents were used in high quality unless otherwise stated. All complement proteins, alternative and classical pathway buffers, detection antibodies, and red blood cells were obtained from Complement Technologies (Tyler, TX) or Quidel Corporation (San Diego, CA). Flow cytometry antibodies were obtained from BD Biosciences, San Jose, CA. TMB substrate was obtained from Kirkegaard & Perry Limited, Gaithersberg, MD. All secondary antibodies were obtained from American Qualex, San Clemente, CA, BSA and other reagents were obtained from Sigma-Aldrich, St Louise, MO.

[0095] ELISA plate readers (SpectraMax 190 and 250) were obtained from Molecular Devices and the flow cytometer was a FACS Calibur. The Varity 3D program was used for data analysis. Curve fitting was performed using the MicroCal Origin program. Kinetic tests for hemolysis were run using SectraMax, Molecular Devices. ELISA plates were obtained from Corning Costar, Lowell, MA.

[0096]The humanized chim...

Embodiment 2

[0100] Example 2: Anti-C3b IgG does not inhibit the interaction of properdin C3b

[0101] Anti-C3b IgG has a low pM to low nM affinity for C3b. Antibodies and fragments thereof bind C3b and C3c with high affinity. These antibodies and fragments thereof do not inhibit the binding of properdin to C5. Polystyrene microtiter plates were coated with human factor C3b in phosphate buffered saline (PBS) overnight at 4°C. After aspiration of the C3b solution, wells were blocked with 1% bovine serum albumin (BSA) in PBS (Sigma-Aldrich, St. Louis, Mo.) for 1 hour at room temperature. Wells with no peptide or C3b coating served as background controls. Aliquots of monoclonal anti-C3b antibodies IgG, Fab2, and Fab in blocking solution (containing 2 nM biotinylated properdin) were added to C3b-coated wells and incubated for 1 hour to allow binding to occur . After an incubation period of 1 hour at room temperature, the plates were washed 5 times with PBS and incubated with peroxidas...

Embodiment 3

[0103] Example 3: Anti-C3b IgG, F(ab')2, and Fab inhibit alternative pathway (AP)-dependent rabbit red Cell (rRBC) lysis

[0104] The present test for erythrolysis is based on the formation of terminal complement complexes on the rRBC surface. As a result, the rRBCs dissolve. The programmed decrease in light dispersion at 900 nm is a direct measure of erythrocyte lysis. Typically, rRBCs contain 5mM MgCl 2 The gel was incubated with normal human serum in barbiturate buffer. Under these conditions, the surface of rRBCs triggers activation of the alternative pathway in normal human serum. Activation of the alternative pathway leads to the formation of the C5b-9 complex on the surface of rRBCs. Agents that inhibit C5b-9 complex formation are expected to inhibit cell lysis. In order to evaluate the effect of anti-C3b antibody and its fragments, various concentrations of IgG, F(ab') 2 and Fab were incubated with normal human serum (10% NHS) in AP buffer with a fixed conc...

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PUM

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Abstract

A method of inhibiting complement activation mediated by C3b inhibitors in a subject is provided. The method includes administering a C3b inhibitor to the subject to inhibit at least one of C3b binding to factors B and properdin, to inhibit C3 cleavage, to inhibit the activation of neutrophils, monocytes, platelets, and endothelium; or to inhibit the formation of C3a, C5a, and MAC.

Description

[0001] related application [0002] This application claims priority to U.S. Provisional Application Serial No. 61 / 619,860, filed April 3, 2012, which claims priority to U.S. Patent Application Serial No. 12 / 532,740, the subject matter of which is incorporated herein by reference in its entirety. technical field [0003] The present application relates to humanized chimeric antibodies and antigen-binding fragments thereof having complement pathway inhibitory function, which antibodies and antigen-binding fragments thereof have reduced effector function and immunogenicity. The humanized chimeric monoclonal antibody of the present invention selectively blocks the binding of Factor B to C3b, but does not inhibit the classical activation pathway. These antibodies are unable to inhibit the interaction of C3b with C5 and thus have a unique function in inhibiting the alternative pathway. Such antibodies are useful in treating indications of disease in which the alternative complem...

Claims

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Application Information

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IPC IPC(8): C07K16/18C07K16/42A61K39/395A61P29/00A61P37/00
CPCA61P11/00A61P11/06A61P19/02A61P25/00A61P27/02A61P29/00A61P31/12A61P31/14A61P31/16A61P31/22A61P37/00A61P37/02A61P37/06C07K16/18C07K2317/24C07K2317/54C07K2317/55C07K2317/76C07K2317/92C07K2317/21C07K2317/565
Inventor R·班萨尔
Owner NOVELMED THERAPEUTICS
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