Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-09-07
2003-10-28
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S137100, C424S141100, C424S143100, C424S152100, C424S153100, C424S172100, C424S173100, C530S387100, C530S387500, C530S388100, C530S388200, C530S388220, C530S388700, C530S389100, C530S389600
Reexamination Certificate
active
06638506
ABSTRACT:
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the priority of PCT International: Application No. PCT/DE97/02883 under 35 U.S.C. §371, filed on Dec. 10, 1997, the whole of which is hereby incorporated by reference herein.
FIELD OF THE INVENTION
The invention relates to the use of substances having a well-directed, i.e. selective, effect on a certain receptor family (Fc&ggr;R) or on those immune system cells with defined surface characteristics which express said receptor and whose presence—in examinations performed by the applicant—has been found to be specific, or its number specifically increased, in the case of amyotrophic lateral sclerosis.
BACKGROUND OF THE INVENTION
Amyotrophic lateral sclerosis (in the following referred to as ALS, its abbreviation) is a neurodegenerative disease of the human motoneuron system which usually takes a lethal course within 3 to 5 years, whose causes have not been determined etiologically and for which there is no, or no significant, therapy as yet. The progressive decay of nerve cells of the first and second motor neurons are the cause of an increasing paralysis of the voluntary muscles, eventually leading to a total walking inability and the increasing paralysis of the respiratory musculature. It has largely been proven that cellular and humoral (antibody-mediated) immunological processes play an important role, if yet unexplained in the individual case, in the pathogenesis of ALS. Worldwide, the prevalence of this disease is 4 in 100,000 and its incidence is 1 in 100,000 inhabitants.
Numerous examination results seem to imply that immunological mechanisms are at play in the pathogenesis of amyotrophic lateral sclerosis. The following findings substantiate this assumption: Cytotoxic serum activity of ALS patients in neuronal cell cultures; serum immunoglobulin G (IgG) toxicity against spinal and cortical neurons as well as voltage-dependent calcium channel proteins; cytotoxicity of the cerebrospinal fluid of ALS patients against glutamate receptors; changes of the serum concentration of IgG isotypes; immune response of peripheral blood lymphocytes of ALS patients to isolated cell membranes; detection of invasive immune system cells in the motoneuron system of ALS patients. Here, these cells seem to be involved in the motoneuron damaging mechanisms (the quotations of the individual above data can be found in: Westarp, M. E. et al., Neurosci. Lett. 173, 124-126, 1994).
Although this data seems to imply a probable involvement of the cellular immune system in ALS, it has been impossible so far to detect definite quantitative or qualitative changes in the cellular immune system in the case of ALS. In particular, no ALS specific cell types have so far been found in the blood of ALS patients which would be identifiable by their molecular cell surface characteristics and clearly differ from immune cells of healthy experimentees or present in other neurological diseases. Nevertheless, countless therapies involving medication with a relatively broad effectivity as well as an undirected action were attempted in order to suppress or at least modulate immune functions. However, any such therapy attempt has remained without ascertained therapeutical success (cf. e.g. Brown, R. H. et al.: Arch. Neurol. 43, 383-384, 1986; and e.g. Dalakas, M. C. et al.: Arch. Neurol. 51, 861-864, 1994). A disadvantage of such approach is that these forms of therapy (blind or unaware of specific cell parameters with ALS) are not well-directed, i.e. they do not block or suppress exclusively those cell types which are specifically present, or present in significantly increased numbers, in ALS patients.
Tests performed by the applicant have shown that the blood of ALS patients contains mononucleic cells of the immune system which are not found with any other neurological disease or in healthy persons (ALS specific immune cells, cf. Table 1). Contrary to the immune cell types so far observed to be present in increased numbers in ALS patients which are known as prior art (Schubert, W.; Neurosci. Lett. 198, 29-32, 1995), the cell types discovered according to the invention and listed in Table 1 are totally ALS specific. These cell types express receptors for immunoglobulins (Fc&ggr; receptors) preferably for immunoglobulin G (IgG) of under-class 1 (IgG1) and 3 (IgG3) (in the following referred to as Fc&ggr;RIII). The increased number, or the ALS specific occurrence, of said immune cells is an explanation of the hitherto unexplained reduction of IgG1 and IgG3 in the serum of patients diagnosed with ALS which was reported e.g. by Westarp et al. (Westarp, M. E. et al., Neurosci. Lett. 173, 124-126, 1994): Fc&ggr;RIII receptors selectively bind to these immunoglobulins, i.e. a multiplication of cells expressing said receptors (as discovered in applicant's own studies) will result in increased binding to IgG1 and IgG3 and thus an IgG1-IgG3 clearance in this disease. In applicant's own studies, it has been found for the first time that these Fc&ggr; receptor-positive cells exhibit a series of molecular activation characteristics on the cellular surface and, when cultured, will cause damage to, or even the destruction of, nerve cells. These cells are therefore directly involved in the pathomechanism of ALS and, as a cellular form, for the first time constitute a concrete target structure for a well-directed, i.e. specific, therapy with immunoactive substances.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is therefore based on the discovery of Fc&ggr; receptor positive, in particular Fc&ggr;RIII positive, activated cellular forms in the blood stream which are ALS specific, or significantly increased in number in the case of ALS, and relates to a use of substances for the selective suppression, destruction or selective functional blocking of said cellular forms, or blocking or functional inactivation of Fc&ggr; receptors, by infusion or injection of defined substances as specified in claim 1.
Fc&ggr; receptors have been known for quite some time in immunology. There are three different, yet related classes of human Fc&ggr; receptors: Fc&ggr;RI, Fc&ggr;RII and Fc&ggr;RIII. The amino acid sequences of the members of this receptor family as well as the genes coding for said receptors are known: Fc&ggr;RI (Allen, J. M., Seed B.: Science 243, 378-380, 1989), Fc&ggr;RII (Ravetch, J. V,. Kinet, J. -P.: Annu. Rev. Immunol. 9, 457-492, 1991), Fc&ggr;RIII (Ravetch, J. V., Perussia, B.: J. Exp. Med. 170, 481-497, 1989). Most subtypes of these three receptor classes are anchored in the cell membrane of certain immune cells. However, all three classes also contain soluble receptor proteins, i.e. proteins not anchored in the cell membrane, which are naturally released by immune cells. The mechanisms are different, however. Soluble Fc&ggr;RI receptors are generated by a stop codon in the extracellular domain. Soluble Fc&ggr;RII receptors are generated by alternative RNA splicing, and soluble Fc&ggr;RIII receptors are generated by proteolytic splitting of the receptor anchored in the cell membrane (cf. summarizing survey in: Jan, G. J. et al.: Immunology Today, 14, 215-221, 1993).
Said Fc&ggr; receptors are particularly relevant for a number of important immunologic functions. All these functions are based on the fact that Fc&ggr; receptors specifically bind to G immunoglobulins. The binding of such immunoglobulins to Fc&ggr; preceptors stimulates or triggers a variety of different cellular activities: Phagocytosis, endocytosis, antibody-dependent cell-mediated cytotoxicity, the release of soluble, inflammation-promoting factors (mediators) as well as the increase of antigen presenting mechanisms. G immunoglobulins bind to Fc&ggr; receptors via their Fc parts. If G immunoglobulins for example bind to Fc&ggr; receptors anchored on the surface of certain immune cells in this manner, said immune cells will then be capable of binding very specifically to antigen-bearing target cells and destroying them. These mechanisms probably play an important pathogenetic part
Gambel Phillip
Roark Jessica H.
Weingarten Schurgin, Gagnebin & Lebovici LLP
LandOfFree
Method of blocking cytotoxic activity in patients with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of blocking cytotoxic activity in patients with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of blocking cytotoxic activity in patients with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3171101