Autoantibody inhibitors

Details Autoantibody inhibitors Autoantibody inhibitors

1999-08-26

2001-12-25

Gambel, Phillip (Department: 1644)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Binds specifically-identified oligosaccharide structure

C424S130100, C424S141100, C424S809000, C424S810000, C424S133100, C424S152100, C424S172100, C514S903000

Reexamination Certificate

active

06333033

ABSTRACT:

FIELD OF THE INVENTION
The field of this invention is polypeptide autoantibody inhibitors and methods of use thereof.
BACKGROUND
Multiple sclerosis (MS) is a chronic relapsing remitting disorder disease of the central nervous system that affects 350,000 Americans and, second to trauma, is the leading cause of disability among young adults. MS is an immune-mediated disorder characterized pathologically by perivenular white matter infiltrates comprised of macrophages and mononuclear cells (inflammation), and destruction of the myelin sheaths that insulate nerve fibers (demyelination).
Experimental allergic encephalomyelitis (EAE) in rodents has been the most widely employed model for testing of therapies for human MS. These traditional disease models for MS generally have promoted the concept that MS is a T-cell-mediated disorder. However, the autoantigens that serve as targets for the immune attack have not been identified and the molecular mechanisms implicated in myelin damage remain uncertain. While it is clear that CNS inflammation in EAE is initiated by autoagressive T-cells that recognize myelin antigens in the context of class II-MHC molecules, many of the models lack the early demyelinating component of the MS lesion. B-cell activation and antibody responses appear necessary for the full development of EAE and earlier studies on immune mediated demyelination using myelinated cultures of CNS tissue have implicated humoral factors as effector mechanisms. Thus, it is not surprising that rodent EAE has not been a robust predictor of efficacy in humans as fundamental differences in the clinical course, pathology, and immunologic response to myelin proteins distinguish rodent EAE from human MS.
Recently a novel MS-like illness in an outbred nonhuman primate, the common marmoset
Callithrix jacchus
, has been defined. The marmoset EAE has a prominent, MS-like early demyelinating component which requires the presence of myelin-specific autoantibodies, and has afforded an opportunity to understand the interactions between these antibodies and their target antigens on myelin. Characteristics of the model include: a. Mild clinical signs and a relapsing remitting course similar to MS; b. A primary demyelinating pathology with early gliosis indistinguishable from MS lesions (demyelinating plaques); c. Natural bone marrow chimerism permitting successful adoptive transfer of encephalitogenic (e.g disease-inducing) T-cell clones and lines; d. Diversity of the encephalitogenic repertoire of T-cells reactive against fit the major myelin protein myelin basic protein (MBP); e. Different disease phenotypes resulting from immunization with different myelin constituents: in contrast to whole myelin, immunization with MBP produces a non-demyelinating form of EAE; f. Demonstration that demyelination is antibody-mediated but also requires an encephalitogenic T-cell response to facilitate autoantibody access to the nervous system; and, g. A key role of myelin oligodendrocyte glycoprotein (MOG) in plaque formation: adoptive transfer of anti-MOG antibody in non-demyelinating MBP-EAE reproduces fully developed MS-like pathology.
The highly immunogenic properties of MOG (<0.05% of total myelin protein) may be related to its extracellular location on the outermost lamellae of the myelin sheath, where it is accessible to pathogenic antibody in the context of blood brain barrier disruption by encephalitogenic T-cells. The
C. jacchus
model permits precise identification of cellular and humoral immune responses that result in an MS-like lesion in a species with immune and nervous system genes that are 90-95% homologous to humans. The relevance of this model to human MS is emphasized by the recent finding of strong T-cell and antibody responses to MOG in MS patients.
SUMMARY OF THE INVENTION
The present invention is directed to autoantibody inhibitors and methods of use thereof Accordingly, the invention provides methods and compositions for inhibiting pathogenic binding of an autoantibody to an autoantigen and screening for inhibitors of pathogenic binding of an autoantibody to an autoantigen.
In one aspect, the present invention provides a composition comprising a peptide consisting of residues 28-36, 13-21, 62-74, 27-34 or 40-45 of rat, human or marmoset MOG. In a preferred embodiment the MOG polypeptide is directly joined at its N- and C- termini with other than natural human or marmoset MOG flanking residues.
In another aspect, the present invention provides a method of inhibiting pathogenic binding of a MOG specific autoantibody to MOG or an immunodominant epitope thereof.
In yet another aspect, the present invention provides a method of detecting autoantibodies in a tissue sample. In a preferred embodiment a method of identifying autoantibodies against myelin/oligodendrocyte glycoprotein (MOG) within lesions of human MS and
C. jacchus
EAE, where they appear to be directly responsible for the disintegration of the myelin sheaths, is provided.
In a further aspect, the present invention provides a method of screening small molecules or candidate agents capable of binding to an autoantigen and thereby inhibit binding of an autoantibody. The method comprises contacting a solution comprising an autoantigen and an autoantibody, incubating under conditions sufficient to allow the reaction to reach equilibrium, and comparing the binding of the autoantibody in the absence of the small molecule inhibitor or candidate agent to the binding of the autoantibody in the presence of the small molecule inhibitor or candidate agent. In a preferred embodiment the small molecules specifically bind at least one immunodominant epitope of the autoantigen.
In yet another aspect of the invention there is provided a method of inhibiting pathogenic binding of an autoantibody to an autoantigen comprising administering to a host subject to pathogenic autoantigen-autoantibody binding-mediated pathology an effective amount of a composition comprising a fragment of an antibody specific for the autoantigen sufficient to specifically bind the autoantigen and competitively inhibit the binding of an autoantigen-specific autoantibody to the autoantigen, wherein the fragment does not comprise a functional Fc portion of the autoantigen-specific antibody. In a preferred embodiment, the autoantigen-autoantibody binding is associated with a demyelinating disease of the central or peripheral nervous system. In a particular embodiment, the disease is associated with pathogenic autoantibody binding, such as MS, lupus, arthritis or diabetes. In more particular embodiments, the autoantigen is a MOG autoantigen and the fragment is a F(ab′)
2
fragment.
In yet another aspect, the invention also provides methods of screening for an agent which modulates the binding of an autoantibody to an autoantigen. Such methods generally involve incubating a mixture comprising the autoantibody or an auto antibody-specific binding fragment thereof, the autoantigen, and a candidate agent under conditions whereby, but for the presence of said agent, the autoantibody or fragment thereof specifically binds the autoantigen at a reference affinity; detecting the binding affinity of autoantibody or fragment thereof to the autoantigen to determine an agent-biased affinity, wherein a difference between the agent-biased affinity and the reference affinity indicates that said agent modulates the binding of the autoantibody or fragment thereof to the autoantigen. In particular embodiments, the autoantibody or fragment thereof is a F(ab′)
2
fragment; the autoantigen comprises a MOG epitope; and/or the autoantigen comprises a MOG epitope consisting of residues 28-36, 13-21, 62-74, 27-34 or 40-45 of rat, human or marmoset MOG.
DETAILED DESCRIPTION OF THE INVENTION
The following description and examples are offered by way of illustration and not by way of limitation.
The invention provides methods and compositions for inhibiting pathology associated with the binding of an autoantibody to a MOG polypeptide, such as occurs in MS. The general methods comprise th

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