RECOMBINANT FRAGMENTS OF THE HUMAN ACETYLCHOLINE RECEPTOR AND THEIR USE FOR TREATMENT OF MYASTHENIA GRAVIS

Abstract: Polypeptides capable of modulating the autoimmune response of an individual to human acetylcholine receptor (hAChR), more particularly polypeptides corresponding entirely or partially to the extracellular domain of hAChR alpha -subunit, are useful in the diagnosis and treatment of myasthenia gravis. Preferred polypeptides are polypeptides corresponding to amino acid residues 1-121 or 122-210 of the hAChR alpha -subunit sequence, and polypeptides corresponding to amino acid residues 1-121, 1-210 or 1-205 of the hAChR alpha -subunit sequence in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR alpha -subunit gene, and fragments, analogs, fused, soluble and denatured forms thereof. DNA molecules encoding said polypeptides are also provided.

Description: RECOMBINANT FRAGMENTS OF THE HUMAN ACETYLCHOLINE RECEPTOR AND THEIR USE FOR TREATMENT OF MYASTHENIA GRAVIS FIELD OF THE INVENTION The present invention relates to polypeptides capable of modulating the autoimmune response to acetylcholine receptor, and more particularly to polypeptides corresponding entirely or partially to the extracellular domain of human acetylcholine receptor α-subunit, which polypeptides are useful in the diagnosis and treatment of myasthenia gravis, and to DNA molecules encoding said polypeptides. ABBREVIATIONS: AChR - acetylcholine receptor; α-BTX - α-bungarotoxin; EAMG - experimental autoimmune myasthenia gravis; GST - glutathione S-transferase; hAChR - human acetylcholine receptor; MG - myasthenia gravis; MIR - main immunogenic region. BACKGROUND OF THE INVENTION Myasthenia gravis (MG) is a human autoimmune disorder characterized by muscle weakness and fatigability. In this disease, antibodies against the acetylcholine receptor (AChR) bind to the receptor and interfere with the transmission of signals from nerve to muscle at the neuromuscular junction [Patrick and Lindstrom, 1973]. The acetylcholine receptor molecule is a transmembrane glycoprotein consisting of five homologous subunits, organized in a barrel-staves-like structure around a central cation channel, in the stoichiometry of either ot2βγδ in fetal, or α2βεδ in mature, muscle [Karlin, 1980; Changeux et al, 1984]. Noda et al. (1983) described the cloning and sequence analysis of human genomic DNA encoding the α-subunit precursor of muscle acetylcholine receptor, and Schoepfer et al. (1988) reported the cloning of the α-subunit cDNA from the human cell line TE671. Human muscle AChR α-subunit exists in two forms, one of which has 25 additional amino acid residues, inserted between positions 58 and 59, that are coded by the 75bp exon p3A [Beeson et al, 1990]. The α-subunit of AChR contains both the site for acetylcholine binding and the main targets for anti-AChR antibodies. The autoimmune response in myasthenia gravis is directed mainly towards the extracellular domain of the AChR α-subunit (amino acids 1-210), and within it, primarily towards the main immunogenic region (MIR) encompassing amino acids 61-76 [Tzartos and Lindstrom, 1980; Tzartos et al., 1987; Loutrari et al., 1992]. The involvement of antibodies directed to the MIR and to the ligand binding site of AChR in the autoimmune process can be assessed by the ability of monoclonal antibodies (mAbs) with these specificities to passively transfer experimental autoimmune myasthenia gravis (EAMG) into animals. Examples of such antibodies are mAb 198, mAb 195, mAb 202 and mAb 35 directed towards the MIR of the extracellular portion of hAChR α-subunit [Sophianos and Tzartos, 1989], and mAb 5.5 directed towards the binding site of AChR [Mochly-Rosen and Fuchs, 1981]. The anti-MIR antibodies exert their effect by crosslinking AChRs on the muscle surface thereby accelerating their degradation, and the anti-binding site mAbs by blocking and competing with acetylcholine [Souroujon et al., 1986; Asher et al., 1993; Loutrari et al., 1992a]. Anti-MIR mAbs have also been shown to accelerate the degradation of AChR in the human cell line TE671 [Loutrari et al., 1992]. MG is currently treated by acetylcholinesterase inhibitors and by non-specific immunosuppressive drugs that have deleterious side effects. It would be preferable to treat MG with a method that involves antigen-specific immunotherapy but leaves the overall immune response intact. One such strategy of specific therapy could involve the administration of derivatives of AChR that do not induce myasthenia but are capable of affecting the immunopathogenic antibodies. However, since the anti-AChR antibody repertoire in myasthenia gravis has been shown to be polyclonal and heterogeneous [Drachman, 1994], the regulation of the disease requires modulation of many antibody specificities. Previous studies at the laboratory of the present inventors were directed towards modulating the anti-AChR response and EAMG by either denatured derivatives of Torpedo AChR, e.g. the reduced and carboxymethylated derivative, RCM-AChR [Bartfeld and Fuchs, 1978], synthetic peptides corresponding to specific regions of AChR [Souroujon et al., 1992; Souroujon et al., 1993], or mimotopes selected from an epitope library [Balass et al., 1993]. The Torpedo RCM-AChR did not induce EAMG in rabbits and was effective in suppressing the disease. However, RCM-AChR did induce EAMG in rats. The experiments carried out with the synthetic peptides and mimotopes were only partially successful in neutralizing MG autoimmune response, probably due to the incorrect folding of the short peptides that were recognized by only a portion of the anti-AChR antibodies. MG is currently diagnosed by testing for antibodies against AChR by radioimmunoassay wherein the antigen is crude AChR extracted from human muscle or TE671 cells. This test presents some drawbacks, namely the antigen is not readily available and, in addition, the antibody titers detected are not well correlated with disease severity. Thus, both a safe and effective treatment for MG, as well as a reliable and convenient diagnosis test, are much in desire. SUMMARY OF THE INVENTION It has now been found according to the present invention that polypeptides comprising sequences corresponding to the entire extracellular domain of the human AChR α-subunit, or to fragments thereof, are capable of modulating the autoimmune response to AChR. Said polypeptides, herein referred to as "biologically active" polypeptides, were found to affect the antigenic modulation of AChR in TE671 cells in vitro, and to modulate the course of EAMG in vivo; they were effective in suppressing the disease both in EAMG that was passively transferred by monoclonal anti-AChR antibodies, and in EAMG that was actively induced by immunization with AChR, while they did not induce any symptoms of MG in the rat model system; they were further successful in both preventing EAMG and in suppressing an ongoing disesase when administered nasally or orally to model rats . Thus, the present invention provides, in one aspect, a polypeptide capable of modulating the autoimmune response of an individual to acetylcholine receptor, said polypeptide being selected from the group consisting of: (i) a polypeptide corresponding to amino acid residues 1-210 of the human acetylcholine receptor (hAChR) α-subunit sequence depicted in Fig.l (herein "Hαl-210"), in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2 (herein "Hαl-210+p3A"); (ii) a polypeptide corresponding to amino acid residues 1-205 of the hAChR α-subunit sequence depicted in Fig.l (herein "Hal -205"), in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2 (herein "Hαl-205+p3A"); (iii) a polypeptide corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l (herein "Hαl-121"); (iv) a polypeptide corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l, in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene, depicted in Fig.2 (herein "Hαl-121+p3A"); (v) a polypeptide corresponding to amino acid residues 122-210 of the hAChR α-subunit sequence depicted in Fig.l (herein "Hαl22-210"); (vi) a polypeptide as in (i) to (v) or the polypeptide Hal -210 in which one or more amino acid residues have been added, deleted or substituted by other amino acid residues in a manner that the resulting polypeptide is capable of modulating the autoimmune response to acetylcholine receptor; (vii) a fragment of a polypeptide as in (i) to (vi), which fragment is capable of modulating the autoimmune response to acetylcholine receptor; (viii) a polypeptide comprising two or more fragments as in (vii) fused together with or without a spacer; (ix) a polypeptide or a fragment as defined in (i)-(viii) or the polypeptide Hal -210 fused to an additional polypeptide at its N- and/or C-terminal; and (x) soluble forms, denatured forms, chemical derivatives and salts of a polypeptide or a fragment as defined in (i)-(ix). Preferred polypeptides according to the invention are Hal -121, Ha 122-210 and, in particular, Hαl-210+p3A, Hαl-121+p3A, Hαl-205+p3A optionally fused to an additional polypeptide e.g. glutathione S-transferase (GST), and Hal -210 similarly fused. Preferably a fragment of Hαl-121 comprises at least the amino acid residues 61-76 of the hAChR α-subunit sequence depicted in Fig.l, and a fragment of Hαl22-210 comprises at least the amino acid residues 184-210 of the hAChR α-subunit sequence depicted in Fig.l . In another aspect, the invention encompasses a DNA molecule coding for a biologically active polypeptide according to the invention. Said DNA molecules may be selected from genomic DNA, cDNA or recombinant DNA or may be synthetically produced. In particular the invention provides a DNA molecule comprising a nucleotide sequence coding for a polypeptide of the invention, said DNA molecule being selected from the group consisting of: (i) a DNA molecule comprising the sequence of nucleotides 1 to 630, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175; (ii) a DNA molecule comprising the sequence of nucleotides 1 to 615, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175; (iii) a DNA molecule comprising the sequence of nucleotides 1 to 363 depicted in Fig.l ; (iv) a DNA molecule comprising the sequence of nucleotides 1 to 363 depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175; (v) a DNA molecule comprising the sequence of nucleotides 364 to 630 depicted in Fig.1 ; (vi) DNA molecules which are degenerate, as a result of the genetic code, to the DNA sequences of (i) to (v) and which code for a polypeptide coded for by any one of the DNA sequences of (i) to (v); (vii) a DNA molecule having a coding nucleotide sequence which is at least 70% homologous to any one of the DNA sequences of (i) to (vi) or to the DNA sequence coding for Hal -210; (viii) a DNA molecule as in (i) to (v) or the DNA molecule coding for Hal -210 in which one or more codons has been added, replaced or deleted in a manner that the polypeptide coded for by said sequence is capable of modulating the autoimmune response to acetylcholine receptor; (ix) a fragment of a DNA molecule as in (i)-(viii) which codes for a polypeptide capable of modulating the autoimmune response to acetylcholine receptor; (x) a DNA molecule comprising two or more fragments of (ix) fused together with or without a spacer, and which codes for a polypeptide capable of modulating the autoimmune response to acetylcholine receptor; and (xi) a DNA molecule comprising a nucleic acid sequence as defined in (i)-(x) or the DNA sequence coding for Hal -210 fused to additional coding DNA sequences at its 3' and/or 5' end. Preferred DNA molecules according to the invention are those comprising the sequences of nucleotides 1-363 and 364-630, depicted in Fig.l, coding for Hαl-121 and Hal 22-210, respectively, and particularly the sequences of nucleotides 1-630, 1-615 and 1-363, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175, said DNA molecules coding, respectively, for Hαl-210+p3A, Hαl-205+p3A and Hαl-121+p3A that comprise the additional 25 amino acid residues coded for by the p3A exon of the hAChR α-subunit gene, as well as a DNA molecule coding for Hal -210 fused to additional coding DNA sequences e.g. the sequence coding for GST. Preferably, a fragment DNA molecule according to the invention codes for a polypeptide comprising at least the amino acid residues 61-76 and/or 184-210 of the hAChR α-subunit sequence depicted in Fig.1. In still other aspects, the invention provides replicable expression vehicles comprising a DNA molecule of the invention and prokaryotic or eukaryotic host cells transformed therewith. A further aspect of the invention relates to a process for preparation of the polypeptides of the invention comprising culturing, under conditions promoting expression, host cells transformed by replicable expression vehicles comprising the DNA molecules of the invention, and isolating the expressed polypeptides. In yet another aspect, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a polypeptide selected from the group consisting of the polypeptides of the invention and a polypeptide comprising the amino acid residues 1-210 of the hAChR α-subunit depicted in Fig. 1 (Hal -210), soluble . forms, denatured forms, salts and chemical derivatives thereof. The polypeptide Hal -210 was previously described in the literature as a polypeptide which induces myasthenia gravis [Lennon et al., 1991], but the use of this polypeptide for alleviation and/or treatment of myasthenia gravis is herein disclosed for the first time. In still another aspect, the present invention provides methods for diagnosis and for alleviation and/or treatment of myasthenia gravis using the polypeptides and pharmaceutical compositions of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 depicts the nucleotide sequence (upper line) and the amino acid sequence coded thereby (lower line) corresponding to the extracellular domain of the hAChR α-subunit (amino acid residues 1-210). Fig. 2 depicts the nucleotide sequence (upper line) and amino acid sequence coded thereby (lower line) corresponding to the p3A exon of the hAChR α-subunit gene. Figs. 3A-C depict Coomassie staining (3 A) and Western blots with mAb 198 (3B) or mAb 5.5 (3C) of Hαl-210+p3A, Hal -210, Hal-121+3pA, Hal-121 and Hαl22-210 fused to glutathione S-transferase (GST) at the N-terminal (lanes 1 to 5, respectively). GST alone (lane 6) served as a control. Fig. 4 depicts results of an ELISA assay showing binding of mAb 198 to Hαl-210+p3A (filled squares), Hαl-210 (open squares), Hαl-121+p3A (filled circles) and Hαl-121 (open circles). Fig. 5 depicts results of an ELISA assay showing binding to Hαl-210+3pA of mAb 198 (filled squares), mAb 5.5 (open triangles), mAb 195 (filled "upside down" triangles), mAb 202 (filled "upright" triangles) and mAb 35 (open circles). Fig. 6 depicts results of an ELISA assay demonstrating inhibition of mAb 198 (O.lμg/well) binding to AChR by the following polypeptides: Hα 1-210+3 pA (filled squares), Hαl-210 (open squares), Hαl-121+3pA (filled circles), Hαl-121 (open circles) and GST (filled triangles), at concentrations of 0.05-10 μg/well. Fig. 7 depicts the inhibition effect of the polypeptides of the invention on AChR degradation induced by mAb 198. TE671 cells were incubated with (a) medium, (b) 1 μg/ml mAb 198, (c-g) 1 μg/ml of mAb 198 preincubated with either Hαl-121 (hatched columns) or with Hαl22-210 (dark columns) at concentrations of 10 (c), 25 (d), 50 (e), 100 (f) and 200 (g) μg/ml. Residual AChR was monitored by measuring α-bungarotoxin (α-BTX) binding sites. Fig. 8 depicts the effect of Hαl-121+p3A on AChR degradation induced by different mAbs. Residual AChR was monitored by measuring α-BTX binding sites. TE671 cells were incubated with medium alone (leftmost column) or with added mAb 198 (1 μg/ml), mAb 35 (1 μg/ml), mAb 195 (5 μg/ml) or mAb 202 (5 μg/ml) either without (dotted columns) or following preincubation of the mAbs with Hαl-121+p3A (hatched columns). Figs. 9A-B depict the effect of nasal administration of Hαl-210+p3A and Hαl-121+p3A on T cell responses to Torpedo AChR (0.25 μg/ml) (9A), and IL-2 production in culture (9B). Both assays were performed on cells pooled from lymph nodes taken 5 weeks after immunization with AChR from treated and control animals. Figs. 10A-B depict the effect of nasal pretreatment on the antibody titers to Hαl-210+p3A (10A) and to rat AChR (10B), in sera from animals treated with RECTIFIED SHEET (RULE 91) Hαl-210+p3A or control vehicle (GST), at 4 and 8 weeks after immunization with Torpedo AChR Figs. 11 A-B depict the effect of oral pretreatment with Hαl-210+p3A and Hαl-205+p3A on the mean clinical score of EAMG (11 A) and on body weight (1 IB). Figs. 12A-B depict the effect of oral pretreatment with Hαl-210+p3A and Hαl-205+p3A on T cell responses to Torpedo AChR (0.25 μg/ml) (12A), and on the antibody titers to rat AChR (12B). Figs. 13 A-B depict the effect of oral treatment with denatured Hαl-205+p3A on an ongoing EAMG. The mean clinical score (13 A) and the mean body weight change (1 B) were monitored for 7 weeks following the beginning of treatment. DETAILED DESCRIPTION OF THE INVENTION Patients with the neuromuscular disease myasthenia gravis are characterized by the pathogenic autoantibodies they develop directed towards AChR [Aharonov et al., 1975]. The α-subunit of AChR appears to be the prime target for these pathogenic autoantibodies, and within it especially the extracellular domain. Human muscle AChR α-subunit exists as two isoforms consisting of 437 and 462 amino acid residues [Beeson et al., 1990]. The two isoforms are identical in their amino acid composition except for a sequence of 25 additional amino acid residues inserted after position 58 in the extracellular domain of the longer variant. These additional amino acids are encoded by the 75bp exon p3A. It was found according to the present invention that the polypeptides herein designated Hαl-210. Hαl-210+p3A, Hαl-121, Hαl-121+p3A, Hαl-205+p3A and Hαl22-210 are capable of modulating the autoimmune response to AChR and of suppressing experimental myasthenia gravis in animal models. The present invention thus relates to the novel polypeptides Hal -121, Hal-121+p3A, Hal22-210, Hal-205+p3A and Hαl-210+p3A as well as to analogs, fragments, fused derivatives, chemical derivatives and salts thereof, and to novel analogs, fragments, fused derivatives, chemical derivatives and salts of the peptide Hal -210. Analogs according to the invention are polypeptides in which one or more amino acid residues have been added to, replaced in or deleted from the original polypeptide in a manner that the resulting polypeptide retains its biological activity. These analogs may be prepared by 8 RECTIFIED SHEET (RULE 91) known synthesis procedures and/or by genetic engineering methods, for example by expressing a DNA molecule modified by site-directed mutagenesis. Biologically active fragments of the polypeptides encompassed by the present invention include preferably polypeptides comprising at least the amino acid residues 61 to 76 and/or 184 to 210 of the hAChR α-subunit sequence, representing, respectively, the main immunogenic region (MIR) and the acetylcholine binding site of the hAChR α-subunit. A fragment comprising at least amino acid residues 61 to 76 is a preferred fragment according to the invention. Also included in the invention are polypeptides comprising two or more fragments as mentioned above which are fused together with or without a spacer. Chemical derivatives of polypeptides of the invention include modifications of functional groups at side chains of the amino acid residues, or at the N- and/or C-terminal groups. Examples of such derivatives include, but are not limited to, esters of carboxyl and hydroxy groups, amides of carboxyl groups generated by reaction with ammonia or with primary or secondary amines and N-acyl derivatives of free amino groups. Cyclic forms of the polypeptides containing a disulfide bridge between two cysteines residues to stabilize the molecule are also encompassed by the invention. The salts of the polypeptides of the invention are pharmaceutically acceptable, i.e. they do not destroy the biological activity of the polypeptide, do not confer toxic properties on compositions containing them and do not induce adverse effects. The term "salts" refers to salts of carboxyl groups as well as to acid addition salts of amino groups of the polypeptide molecule. A polypeptide of the invention, or a fragment thereof, may be fused to an additional polypeptide at its N- and or C-terminal. For example, recombinant polypeptides were prepared where Hαl-210, Hαl-210+p3A, Hαl-121, Hαl-121+p3A or Hαl22-210 were fused to glutathione S-transferase (GST) at the N-terminal, and these molecules were capable of modulating the immune response to AChR. Other polypeptides may be fused to the N- and/or C-terminal of a polypeptide of the invention provided that the fusion does not significantly impair the three dimensional structure of the resulting polypeptide in a way that prevents it from being recognized by anti-AChR antibodies. A polypeptide according to the invention corresponding entirely or partially to the extracellular domain of the hAChR α-subunit should be capable of affecting the immunopathogenic response without inducing myasthenia gravis by itself. In order to neutralize the anti-AChR antibodies, the polypeptide may be at least partially correctly folded, so that it will be recognized by said antibodies. Furthermore, since the anti-AChR antibody repertoire in myasthenia gravis has been shown to be polyclonal and heterogeneous [Drachman, 1994], the regulation of myasthenia gravis requires modulation of many antibody specificities. The recombinant polypeptides according to the invention have, indeed, shown to have a broad specificity as demonstrated by their ability to protect AChR in TE671 cells against antigenic modulation induced by a series of anti-AChR mAbs (Fig 8) or by polyclonal anti-AChR antibodies from myasthenic rats (data not shown). The three-dimensional arrangement of a polypeptide of the invention seems to be sometimes of crucial importance for its biological activity. It was shown in several experiments (see Figs. 3B, 3C, 4 and 6) that the polypeptides comprising the additional 25 amino acid residues coded for by the exon p3A, namely Hαl-121+p3A and Hαl-210+p3A, bind to anti-AChR antibodies better than the shorter variants Hαl-121 and Hal -210, and are also more potent in their protection effect in TE671 cells in vitro and in EAMG in vivo. Thus Hαl-121+p3A and Hαl-210+p3A are the most preferred polypeptides according to the invention. The major binding sites of the anti-AChR mAbs inhibited by the polypeptides of the invention do not seem to reside within the stretch of amino acids encoded by the p3A exon. Therefore, it seems likely that the different specificity of these mAbs towards the polypeptides with and without the p3A exon encoded sequence reflects conformational changes due to the presence of said extra encoded sequence. Conformational differences could also explain why mAb 198 binds well to the polypeptides containing the p3A exon encoded sequence, but was unable to immunoprecipitate an oocyte-expressed α-subunit containing this sequence [Newland et al., 1995]. A polypeptide of the invention may be produced by means of recombinant technology or synthetically employing methods well-known in the art. Recombinant polypeptides according to the invention are prepared by culturing host cells transformed by a suitable expression vector containing a DNA molecule of the invention under conditions promoting expression, and isolating the expressed polypeptide, using standard techniques well known in the art (see, for example, Sambrook et al., 1989; Ausubel et al., 1993). Soluble forms of the polypeptides that constitute a preferred embodiment of the invention may be generated by suitable chemical modification of natural amino acid residues in the polypeptide, or by substitution of said natural amino acid residues by suitable hydrophilic natural or non-natural amino acids. Alternatively, solubility may be induced by fusion of a polypeptide of the invention to a highly soluble polypeptide partner, such as GST, immunoglobulin or a fragment thereof, maltose binding protein (MBP), thioredoxin or influenza non-structural protein 1 (NS1). The additional polypeptide may be fused at the N- or C-terminal of the polypeptide of the invention, and it should not significantly impair the three dimensional structure of the polypeptide corresponding to the hAChR α-subunit domain. The fused polypeptide of the invention may be used as such, or it may be subjected to further processing in which an active polypeptide of the invention is released. Insertion of a target sequence that is cleavable by specific proteases, such as V8 protease, enterokinase, thrombin or factor Xa, enables the release of the original polypeptide from the recombinant expressed fused polypeptide. A DNA molecule according to the invention comprises a nucleotide sequence coding for a biologically active polypeptide of the invention. The DNA molecule may be from any origin including non-human sources, and may be selected from genomic DNA, cDNA, recombinant DNA, PCR-produced or synthetically produced DNA. Preferred DNA molecules are those comprising the sequence of nucleotides 1-363 and 364-630 of the hAChR α-subunit (depicted in Fig.l) coding for Hαl-121 and Hαl22-210, respectively, and particularly the sequences of nucleotides 1-630, 1-615 and 1-363 of the hAChR α-subunit in which the sequence of the p3A exon of the hAChR α-subunit gene (depicted in Fig.2) is inserted between nucleotides 174 and 175, hence coding, respectively, for Hαl-210+p3A, Hαl-205+p3A and Hαl-121+p3A. A fused DNA molecule according to the invention comprises a nucleic acid sequence coding for a polypeptide of the invention in fusion to additional coding DNA sequences at its 3' and/or 5' end. The added DNA sequence may code for a polypeptide endowing the expressed fused polypeptide with favourable characteristics for its purification or for performing its biological activity, i.e. conferring on the original polypeptide molecule a preferred configuration or high solubility. A DNA molecule of the invention may be directly isolated from human genomic DNA or cDNA by standard means known in the art involving subcloning genomic or cDNA fractions into a replicable vector, amplifying the subcloned fragments, detecting the relevant clones by their hybridization to the DNA molecules of the invention or fragments thereof, followed by their isolation, for example as described in Sambrook et al., eds. "Molecular Cloning: A Laboratory Manual", 2nd ed., Cold Spring Harbor Press, 1989; and in "Current Protocols in Molecular Biology" Current Protocols, Ausubel et al., eds., 1993. DNA molecules which are at least 70% homologous to Hal -210, Hal-210+p3A, Hal-205+p3A, Hal-121, Hal-121+p3A or Hal22-210 may be isolated by subjecting a population of cloned genomic DNA or cDNA molecules to hybridization with the above synthesized DNA molecules or fragments thereof under stringent conditions, and isolating the hybridized clones. The term "stringent conditions" refers to hybridization and subsequent washing conditions conventionally referred to in the art as "stringent" (see Sambrook et al. and Ausubel et al., supra). Alternatively, a DNA molecule of the invention may be PCR-produced as described for example in Example 1 hereinafter. In general, the PCR-production procedure comprises total RNA purification from relevant cells and generation of first strand cDNA by reverse transcriptase, using either an antisense oligonucleotide mixture or oligo (dT) as a primer. A cDNA fragment may be then amplified in a polymerase chain reaction (PCR) using appropriate sense and antisense primers flanking the target cDNA fragment. The PCR primers may include restriction sites to be used for restriction enzyme digestion followed by cloning into a suitable vector. Cloning of a DNA molecule of the invention within an appropriate expression vehicle and expression in a suitable host cell enables production and isolation of a biologically active polypeptide or fragment thereof. For this purpose, the DNA molecule is incorporated into a plasmid or viral vector preferably capable of autonomous replication in a recipient host cell of choice. Optionally, the DNA molecule may be cloned into an expression vector in frame with additional coding sequences at its 5' and/or 3' end, e.g. the pGEX plasmid vectors that contain GST coding sequences fused upstream to the cloning site. The recombinant expression vector is then used to transform an appropriate prokaryotic or eukaryotic host cell that, under inducing conditions, expresses the polypeptide itself or fused to an additional sequence. In the latter case, insertion of a recognition site for a protease, enables at will the release of the cloned polypeptide from the additional fused polypeptide. Vectors used in prokaryotic cells include, but are not limited to, plasmids capable of replication in E. coli, for example, pGEX, and bacteriophage vectors such as λgtl 1, λgtl8-23, Ml 3 derived vectors etc. A vector construct containing the DNA molecule of the invention is then introduced into an appropriate host cell by any of a variety of suitable means known in the art, such as transformation, transfection, lipofection, conjugation, protoplast fusion, electroporation, calcium phosphate precipitation, direct microinjection, etc. Suitable host cells useful in the invention are prokaryotic cells which include, but are not limited to E. Coli, and more preferably, eukaryotic hosts which include, but are not limited to, yeast cells such as Saccharomyces cerevisiae, or insect cell lines, for example Spodoptera frugiperda (Sf9) cells which are commonly used with the baculovirus expression system, or mammalian cells such as Chinese hamster ovary (CHO) cell lines. Eukaryotic cells are the preferred hosts in expression systems for producing the polypeptides of the invention since they can perform the correct post-translational processing to confer the right conformation on said polypeptides. However, since partially correctly folded polypeptides may also be biologically active, prokaryotic expression systems may also be useful, especially for the production of large amount of polypeptides. In another aspect, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a polypeptide selected from a polypeptides of the invention and a polypeptide comprising the amino acid residues 1-210 of the hAChR α-subunit depicted in Fig.l, soluble and denatured forms, salts and chemical derivatives thereof. The pharmaceutical compositions are for use in the alleviation and/or treatment of myasthenia gravis and may be in any suitable form for administration of polypeptides known in the art, e.g. by injection, inhalation, orally, nasally, etc. Appropriate pharmaceutically acceptable carriers include physiological carriers, such as water and oils and excipients such as stabilizers and preservative agents. Saline solutions and aqueous dextrose and glycerol solution are suitable for injectable solutions. The active ingredient may also be prepared as a lyophilized dry compound, possibly as a salt, or as a conjugate with a solid carrier/support such as dextran, natural and modified celluloses, etc. The pharmaceutically acceptable carrier of choice will be determined depending on the route the pharmaceutical composition will be administered. The dosage of the polypeptide and the schedule of the treatment should depend on the route of administration, the patient condition, age and genetic background and will be determined by a skilled professional person. For example, based on animal studies, it was found that dosage ranges of about 1.4 μg - 14 mg and 0.14μg - 0.7 mg/ Kg human body weight are suitable for oral and nasal administration, respectively, in humans. The invention further provides a method for alleviation or treatment of myasthenia gravis which comprises administering to an individual in need thereof an effective amount of a polypeptide selected from a polypeptide of the invention and the polypeptide Hal -210, a soluble form, a denatured form, a chemical derivative or a salt thereof. In contrast to the current methods of treatment of MG using non-specific immunosuppressive drugs, such as steroids, azathioprine or cyclosporine, the method of present invention is directed to an antigen-specific immunotherapy strategy thus suppressing only the adverse autoimmune responses while leaving the overall immune system of the patient intact. Preferred routes of administration of the polypeptides according to the invention are the nasal and oral routes. Nasal tolerization has several advantages as a treatment modality in comparison with oral tolerization: it requires smaller doses of antigen, is more convenient to use and does not require soybean trypsin inhibitor (STI) used in oral tolerance to inhibit the degradation of the antigen in the gastrointestinal tract. Some successful attempts to modulate experimental autoimmune diseases in animal models by nasal administration of the autoantigen have been recently reported. Thus, Weiner et al. [1994] showed that inhalation of aerosols containing myelin basic protein (MBP) abrogated the clinical symptoms of EAE and significantly reduced the CNS inflammation, DTH reaction and antibody titer to MBP; Dick et al. [1993] reported that nasal administration of retinal extract inhibited the induction of experimental allergic uveitis (EAU) by immunization with this extract; and Ma et al. [1995] demonstrated that nasal administration of the antigen Torpedo AChR diminished the incidence and severity of clinical muscle weakness characteristic of EAMG following immunization with said antigen. The pharmaceutical compositions of the present invention are also useful for diagnosis of myasthenia gravis whereby anti-AChR antibodies in the serum of a patient are determined by employing one or more polypeptides of the invention as the test antigen and bound anti-AChR antibody titers indicate the presence of myasthenia gravis. For the diagnostic test, a serum aliquote of a patient is brought in contact with one or more polypeptides, incubated for about 1 h to overnight at 4°-37°C, followed by the determination of the amount of anti-AChR antibodies bound to the polypeptides by quantitative detection assays known in the art. In one embodiment, the diagnostic test is be carried out with immobilized polypeptides in an assay comprising the following steps: (i) immobilization of one or more polypeptides corresponding entirely or partially to the extracellular domain of human acetylcholine receptor on a suitable solid support; (ii) incubation of said immobilized polypeptides of (i) with a serum sample from a patient for 1 h to overnight at 4°-37°C; and (iii) determination of the amount of the anti-AChR antibodies bound to the immobilized polypeptides fragments, whereby detection of anti-AChR titers indicates the presence of myasthenia gravis. The detection of the anti-AChR antibodies may be carried out with labeled anti-human antibodies or labeled Staphilococcus protein A. The label may be a radioactive or fluorescent tag, an enzyme conjugate or another biological recognition tag. Examples of radioactive tags are radioactive isotopes such as 123 1, i S, 32 P, 3 H, l4 C etc, which are detected by a scintillation or a γ-counter or by autoradiography. Fluorescent tags are derived from fluorescent compounds such as fluorescein, isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine, and are detected by exposure of the bound fluorescent labeled antibody to light of the proper wavelength and monitoring the fluorescence. Enzyme conjugates useful for detection purposes include, but are not limited to, maleate dehydrogenase, yeast alcohol dehydrogenase, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, catalase and glucose-6-phosphate dehydrogenase. These enzymes are conjugated to the antibody or to protein A and can be monitored by the product they produce when exposed to the appropriate substrate. The chemical moiety thus released can be detected, for example, by chemiluminescence reaction or by spectrophotometry, fluorometry or visual means. Diagnostic methods based on recognition of biological tags include, for example, coupling of protein A or of the anti-human antibodies to biotin. The biotinylated molecules then can be detected by avidin or streptavidin coupled to a fluorescent compound, to an enzyme such as peroxidase or to a radioactive isotope and the like. In another embodiment, the diagnostic test is carried out with one or more soluble polypeptides pre-labeled by one of the foregoing labels and tags, whereby anti-AChR antibodies of the patient's serum bound to the polypeptides are separated from the free antigen by precipitation of the antigen-antibody complex by Staphilococcus protein A or anti-human antibodies, and anti-AChR titers are determined as described above. The diagnostic assays according to the invention have the advantage of avoiding the need to extract the antigen from human tissues or cells, and also provides a more reproducible and safe way for MG detection. The use as antigens of polypeptides that recognize sub-populations of MG-related antibodies further provides a better means for correlating anti-AChR titers with disease severity. The invention will now be illustrated by the following non-limiting examples and accompanying drawings. EXAMPLES MATERIALS AND METHODS i) Monoclonal antibodies (mAb). The following monoclonal antibodies were used: mAb directed towards the main immunogenic region (MIR) of the extracellular portion of the hAchR α-subunit [Sophianos and Tzartos, 1989]: mAb 198, mAb 195 and mAb 202 elicited in rats against human muscle AChR, and mAb 35 elicited in rats against electric eel AChR, but cross-reacted with AChR from other species, including human; and mAb 5.5 directed towards the binding site of AChR from other species, including human [Mochly-Rosen and Fuchs, 1981], elicited in mouse against Torpedo AChR. ii) Antibody binding assays. Binding of antibodies to AChR or to recombinant polypeptides corresponding entirely or partially to the extracellular domain of the hAChR α-subunit was analyzed by ELISA. Wells of microtiter plates (Maxisorb, Nunc, Neptune, NJ) were coated by incubation overnight at 4°C with either Torpedo AChR (lμg in 100 μl of phosphate-buffered saline (PBS)), or with one of the recombinant polypeptides of the invention (2μg in 100 μl of 50 mM Tris buffer pH 8.0). Coated plates were washed three times with PBS containing 0.05% Tween-20, then wells were blocked by incubation for 1 h at room temperature (R.T.) with 1% bovine serum albumine (BSA) and 1% hemoglobin in PBS, and the coated blocked plates were then washed and incubated overnight at 4°C with different amounts of antibody. For inhibition experiments, each well was coated with 1 μg of Torpedo AChR and a polypeptide of the invention was preincubated with the mAb of choice for 30 min at R.T. before addition to the AChR-coated well. Following a washing step, bound mAb was determined by incubation for 1 h at R.T. with 1 :5000 dilution of alkaline phosphatase (AP)-conjugated goat anti-mouse Igs (Jackson ImmunoResearch Labs, Inc., or Biomakor, Ness-Ziona, Israel). The bound antibody was detected by the enzymatic activity of AP using N-para-nitrophenyl-phosphate as a substrate and determining by a microtiter plate reader at 405 nm the color developed after about 40 min. iii) Determination of AChR content AChR content was determined by measuring α-bungarotoxin (α-BTX) binding sites. Tested samples were derived from (a) muscle preparations or from (b) cells grown in a tissue culture. a) For the muscle preparation, the procedure described by Souroujon et al. [1985] was essentially followed. Briefly, muscle tissue was removed and homogenized in a Sorvall omnimixer for 2 min. at full speed. Two volumes of Tris-HCl buffer, pH 7.5, containing 0.1 M NaCl, 1 mM EDTA, 0.1 mM PMSF and 0.5 mM NaN 3 , were used for homogenization. Homogenates were then centrifuged at 48,000 x g for 1 h, washed once and recentrifuged as above. The homogenates were stirred overnight at 4°C in 2 volumes of the above Tris buffer containing Triton X-100 at a final concentration of 1%. The mixture was then centrifuged for 1 h at 100,000 x g in a Beckman ultracentrifuge and the recovered supematant was stored at -70°C. The AChR in the Triton extracts was determined by measuring the amount of ^^l- - TX that coprecipitated with the receptor in ammonium sulfate at 35% saturation. Unbound toxin was removed by filtration through GF/C filters, and radioactivity retained on filters, i.e. toxin bound to receptor, was measured in a γ-counter. b) For determination of the AChR content in TE671 cells grown in tissue culture, 125j_ α _BTX (final concentration about 2x10"^ M; 10^ cpm) was added to a confluent cell culture in a 30 mm plate and incubated for 1 h at 37°C. The cells were then washed four times with PBS, released with IN NaOH and cell-bound radioactivity was evaluated in a γ-counter, after deducting cpm in a control test tube containing an excess of unlabeled α-BTX (final concentration 10 ~ 6 M). iv) Western blots Electrophoresis of recombinant polypeptides corresponding to the entire or partial extracellular domain of the hAChR α-subunit and their blotting were performed essentially as described [Wilson et al., 1985; Neumann et al., 1985]. The polypeptides were electrophoresed in 10% polyacrylamide gels and transferred to a nitrocellulose membrane. The membrane was preincubated in PBS containing 0.5% hemoglobin for lh at R.T. before addition of lOμg/ml mAbs and incubation was carried out for additional 3 h at 37°C. The membranes were washed 4 times with PBS, once with PBS containing 0.5 % Triton X-100 and then incubated for lh at 37°C with 125ι-.g 0a t_ an ti- m0 use Ig. After five washes, the blots were exposed to an X-ray sensitive film. v) Antigenic modulation in TE671 cells Antigenic modulation experiments were performed in 30-mm 12- well plates using TE671 cell cultures. Cells (2x10^) were plated in Dulbecco Modified Eagles medium (DMEM) containing 2 mM L-glutamine, 10% fetal calf serum (FCS) and antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin and 250 ng/ml amphotericin B), and grown to confluency for 72 h. The antibodies were added in triplicate to culture wells at a concentration of 1 μg/ml (and for mAbs 195 and 202 also at 5 μg/ml) for 3 h. At the end of the incubation, 125ι_ α _Bjχ was added at a final concentration of 2x10"^ M (10$ cpm) for an additional hour. AChR content was determined by measuring ^^l- - TX binding, as described in section (iii) above. In order to test the effect of the polypeptides of the invention on the antigenic modulation induced by the antibodies, the mAbs were preincubated for 1 h at 37°C with said polypeptides (at concentrations of 10-200 μg/ml, as indicated), before their addition to the cell cultures, and the assay continued as described in section (ii) above, vi) Passive transfer of EAMG to rats. Lewis female rats (6 weeks old, approximate weight 120 g) were used for passive transfer experiments, as previously described [Asher et al., 1993]. For the induction of EAMG, 80 μg of the anti-MIR mAb 198 in 1 ml PBS were injected i.p. into each rat. The tested polypeptide (1 mg) was preincubated with mAb 198 for 30 min at R.T., prior to the injection into rats. The rats were observed for myasthenic symptoms and body weight. At 48 h after the administration of mAb, the animals were sacrificed and their leg muscles were removed for determination of the AChR content according to section (iii) above, vii) Induction of EAMG and clinical evaluation Animals were injected once in the hind foot pads with 40 μg of Torpedo AChR emulsified in complete Freund adjuvant (CFA) containing 1 mg/rat Mycobacteήum Tuberculosis (Difco Lab., Detroit, MI). Experimental animals were weighted every week. Clinical EAMG was evaluated as follows: grade 0, no weakness or fatigability; grade 1 , weak grip, fatigability; grade 2, weakness, hunched posture at rest, decrease in body weight, tremolousness; grade 3, severe weakness, marked decrease in body weight, moribund; grade 4: dead. Animals were evaluated weekly up to 7-9 weeks after immunization with Torpedo AChR. Blood samples were obtained from the retroorbital plexus, viii) Lymphocyte proliferation assay Popliteal lymph nodes were aseptically removed and single cell suspensions were prepared in RPMI with 10 mM HEPES. An in vitro T-lymphocyte proliferative assay in response to AChR and the different polypeptides of the invention was performed as follows: Lymph node cells were suspended in RPMI at pH 7.4 containing 10 mM HEPES, supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 0.1 mM nonessential amino acids, 5x10"5 M β-mercaptoethanol and 0.5% normal rat serum, and plated in 96-well flat bottom plates (Coming; 5x10^ cells/well). Increasing concentrations of antigen (0.25 to 10 μg/ml of AChR and 10 to 100 μg/ml of a recombinant polypeptide of the invention), were then added to each well. Plates were incubated at 37°C, in 7.5% C02 and 90% humidity. Proliferation was assayed after 3 days by measuring incorporation of thymidine-methyl-f^H] into cells. Essentially, the cells were incubated with thymidine-methyl-f^H] (Rotem Ind. Ltd, Beer Sheva, Israel; 0.5 mCi/2.5ml) for 24 h and then harvested and counted for radioactivity. Results are presented as incorporated cpm following subtraction of cpm in the presence of medium alone. EXAMPLES Example 1: Preparation of recombinant DNA molecules DNA molecules encoding the biologically active polypeptides Hal -210, Hal-121, Hal22-210, Hal-205+p3A, Hal-210+p3A and Hαl-121+p3A were synthesized as follows: Total RNA was prepared as described [Asher, 1988] from the human TE671 cell line, which expresses the human muscle type nicotinic AChR [Schoepfer et al., 1988]. Preparation of cDNA and the polymerase chain reaction (PCR) were performed as described [Barchan et al., 1992]. The primers employed to amplify cDNA fragments corresponding to the hAChR α-subunit residue 1-210 (Hal -210), with or without the p3A exon (Hal-210+p3A) [Beeson et al., 1990], were constructed with sites that enabled cloning into the fusion protein expression vector pGEX-2T. The primer at the 5' end, CCGGATCCGAACATGAGACC, corresponds to amino acid residues 1-5 of the human AChR α-subunit sequence (nucleotides coding for the first residue are bold), and had a BamHI site (underlined). The primer at the 3' end had an EcoRI site (underlined) and was complementary to the DNA sequence coding for amino acid residues 206-210, CGGAATTCCAGGCGCTGCATGAC. In a similar way the shorter clones Hal -121, Hal-121+p3A and Hal 22-210 were derived by PCR using the above-mentioned Hαl-210 and Hαl-210+p3A clones as templates. For obtaining the two DNA molecules corresponding to amino acid residues 1-121 (with and without the amino acid residues coded by the p3A exon), a primer complementary to the DNA sequence coding for amino acid residues 116-121 with an EcoRI site (underlined) CGGAATTCTGGAGGTGTCCACGTGAT. was used at the 3' end. For the 5' end, the primer described above corresponding to amino acid residues 1-5 was used. For cloning of the DNA coding for Hαl22-210, the primer CCGGATCCGCCATCTTTAAAAGC was used at the 5' end. This primer corresponds to amino acid residues 122-126 (nucleotides coding for residue 122 are in bold) and contains a BamHI site (underlined). The primer used at the 3' end was the same as described above for the DNA molecule coding for Hal -210 (complementary to residues 206-210). The PCR amplified DNA sequences were subcloned into the BamHI-EcoRI sites of pGEX-2T expression vector (Pharmacia) [Smith and Johnson, 1988], in frame with the GST-coding DNA sequences at the 5' end. The clone Hαl-205+p3A was derived by PCR, using as template the cDNA of hAChR from the TE671 cell line. The primer at the 5' end (GGCCATGGGCTCCGAACATGAGACC) corresponded to amino acid residues 1-5 was designed in a way that enabled cloning into a pET8C-derived expression vector by adding a restriction site for NCO I (underlined) the initiation codon ATG. The primer at the 3' end (CCGG TCCTCAAAAGTGRTAGGTGATRTC, where R=A or G) corresponded to the complementary sequence of amino acid residues 200-205, and contained a restriction site for BamHI (underlined) and a stop codon. All the cloned DNA molecules were sequenced in order to verify their sequence and then used to produce the recombinant polypeptides. Example 2: Preparation of recombinant polypeptides The different recombinant DNA molecules subcloned in pGEX-2T plasmid prepared in Example 1 were used to transform competent E. coli cells (strains JM101 or XLl-blue). The transformed bacteria were grown ovemight in LB medium containing ampicillin, then diluted 20 RECTIFIED SHEET (RULE 91) ISA/EP 1 :150 in the medium and further grown for additional 3-5 h. Induction of fused polypeptide expression was achieved by adding 0.5 mM IPTG (isopropyl β-D-thiogalactopyranoside) for 2 h. After expression, the bacterial suspension was centrifuged, cells were lysed by freezing and thawing the pellet and resuspended in PBS (10 ml). The preparation was sonicated for five 15-sec periods, and centrifuged for 15 min at 27,000 x g. The expressed recombinant fused polypeptides were localized in the precipitate, probably in inclusion bodies. The fused polypeptides were solubilized in 1 ml of 9 M urea, the non-soluble fraction was removed by centrifugation for 45 min at 27,000 x g, and the supematant was diluted in 10 ml of 50 mM Tris buffer, pH 8.0 and dialyzed against the same buffer for 48 h with several changes. After ultracentrifugation for 30 min at 100,000 x g, the supernatant was divided into aliquots for storage at -80 C. The protein concentration, determined by the Lowry method, was 1-3 mg/ml, with a yield of 20-50 mg of total protein from one liter of bacterial suspension. The GST-fused polypeptides were isolated using a substrate affinity column according to Smith and Johnson, 1988. A Coomassie brilliant blue staining of the expressed GST-fused polypeptides run on 10%) polyacrylamide gel is shown in Fig. 3A: from left to right, lanes 1-6, Hαl-210+p3A, Hαl-210, Hαl-121+p3A, Hαl-121, Hαl22-210 and GST, appearing to have MW of 52.5, 50.0, 43.7, 41.2, 37.8 and 29.0 kD, respectively, in agreement with the expected MW calculated based on the encoded amino acid sequences of these polypeptides (see Fig.l and Fig.2). Expression of Hαl-205+p3A in the pET8C expression system was performed in a similar procedure using E. coli BL21 strain. Example 3; Immunochemical characterization of the recombinant polypeptides The recombinant polypeptides of Example 2 were further characterized by their binding to various anti-AChR mAbs as assayed by both Western blots (Fig. 3B- mAb 198; Fig. 3C- mAb 5.5) and by ELISA (Fig. 4 and Fig. 5). The recombinant polypeptides (20 μg each) were electrophoresed, blotted onto nitrocellulose membrane, and incubated with different mAbs as described in Materials and Methods, section (iv). Fig. 3B shows that mAb 198, which is directed to the MIR, bound to the polypeptide corresponding to the entire extracellular portion of the hAChR α-subunit (Hal -210) and to its shorter derivative (Hal -121), that contains the MIR, as well as to their variants including the additional p3A encoded sequence Hαl-210+p3A and Hαl-121+p3A. As expected, mAb 198 did not bind to Hal 22-210, which does not include MIR, or to the GST protein itself. The mAb 5.5, which is directed to the binding site of AChR [Mochly-Rosen and Fuchs, 1981], bound to Hal -210, Hal-210+p3A and to Hal 22-210, all including the binding site, but it did not bind to Hal -121, Hal-121+p3A nor to the GST protein (Fig. 3C). As shown, both mAb 198 and mAb 5.5 bound better to the variants containing the sequence encoded by the p3A exon. The binding of mAb 198 to the polypeptides of the invention was also determined in ELISA carried out as described in Materials and Methods section (ii), and the results are shown in Fig. 4. In this assay, as in the Westem blot, mAb 198 bound better to the polypeptides Hαl-210+p3A and Hαl-121+p3A (filled symbols). Therefore, these longer variants were used in further studies. Three other anti-MIR mAbs (mAb 195, mAb 202 and mAb 35) bound to a lesser extent than mAb 198 to all tested polypeptides (not shown). Fig. 5 illustrates the binding of various mAbs to Hαl-210+p3A: Mab 198 (filled squares) showed a very strong binding. MAb 35, which is directed against the MIR and is known to depend on the native conformation of AChR, showed very low binding to the tested polypeptides of the invention (open circles). MAb 5.5 which also depends on the native conformation of AChR, bound well to the tested polypeptides in Westem blots (Fig. 3C), but to a much lesser extent than mAb 198 in ELISA (open triangles). This poor binding of mAbs 35 and 5.5 may indicate that when bound to ELISA plates only a small fraction of the recombinant polypeptide is properly folded. Based on the results of the binding experiments in ELISA, the next step was to test whether the polypeptides of the invention bind to the mAbs also in solution. For that, the ability of the various recombinant polypeptides to inhibit the binding of mAb 198 to Torpedo AChR was tested in ELISA. As shown in Fig 6, Hαl-210+p3A (filled squares) and Hαl-121+p3A (filled circles) inhibited this binding, with IC50 values of 1.8xl0"^M and lxlO'^M, respectively, whereas the GST protein (filled triangles) did not, indicating that the solubilized recombinant fused polypeptides may indeed bind to mAb 198 also in solution. As shown above (Figs. 3B and 4), the variants containing the additional 25 amino acid residues encoded by the p3A exon were more potent in inhibiting mAb 198 binding to AChR than their counterparts lacking this 25-mer. Example 4: Effect of the polypeptides on antigenic modulation of AChR in TE671 cells Muscle AChR loss in myasthenia gravis is caused by accelerated degradation of the receptor, brought about by anti-AChR antibodies, a great portion of which are directed to the MIR. This activity of the antibodies can be demonstrated in vitro in cell cultures such as the human cell line TE671. This human medulloblastoma-derived cell line expresses a functional AChR which binds α-BTX and has the α-subunit of the muscle-type AChR. The ability of the recombinant polypeptides Hal -210 and Hal -121 to protect the AChR on TE671 cells against accelerated degradation of AChR induced by specific anti-AChR α-subunit mAbs, was examined as follows: Anti-MIR mAbs were preincubated for 1 h at 37°C with several concentrations of the recombinant polypeptide and then added to the cells. As a control, the mAbs were preincubated with GST or with the Hal 22-210 polypeptide that does not include the MIR. The inhibition effect of Hal -121 on AChR degradation induced by mAb 198 measured as residual α-BTX binding sites, is illustrated in Fig. 7. MAb 198 causes a reduction of 41% in residual AChR following 3 h incubation with the cells (Fig. 7, lane b). Preincubation with increasing concentrations of Hαl-121 had a dose dependent protection effect against the degradation induced by mAb 198 (Fig. 7, c-g, hatched columns). At a concentration of 100 μg/ml of Hal -121 the TE671 cells were completely protected against the accelerated AChR degradation by mAb 198. Preincubation of mAb 198 with Hαl22-210, which does not contain the MIR, did not affect the antigenic modulation induced by mAb 198 and did not block AChR degradation (Fig. 7, c-g, dark columns). Hal -210, corresponding to the entire extracellular α-subunit domain, had the same effect as the shorter fragment Hal -121 (data not shown). Results of a comparable experiment carried out with other anti-AChR mAbs are shown in Fig. 8. The polypeptide Hαl-121 had a similar protection effect against AChR degradation induced by two other anti-MIR mAbs, mAb 195 and mAb 202, but had a much smaller effect on mAb 35-induced AChR degradation, possibly because of the weak binding of this antibody to Hal -121 in solution (see Fig. 5). Example 5; Modulation by the polypeptides of EAMG passively transferred by mAb 198 The effect of the polypeptides of the invention was also examined in vivo in a well-established animal model disease for myasthenia gravis, designated experimental autoimmune myasthenia gravis (EAMG) [Lindstrom et al., 1976 and 1976a]. In animals such as rabbits, mice, guinea-pigs, monkeys and rats, EAMG can be either passively transferred by anti-AChR antibodies, or actively induced by AChR. In both cases, the treated animals show chronic symptoms of the MG disease, i.e. show general weakness, have a hunched posture, develop a flaccid paralysis of the hind limbs, have difficulties in breathing, in swallowing and in reaching food and water supplied to them, all of which result in weight loss. The animals die from respiratory insufficiency, malnutrition and dehydration. In rats, two distinct episodes of weakness occur, especially after immunization with Torpedo AChR in combination with Mycobacterium tuberculosis (killed) H37 Ra, with an acute phase starting 8-10 days after immunization and a chronic phase starting 3-5 weeks later. Table 1 : Recombinant fragments modulate experimental myasthenia passively transferred by a monoclonal anti AChR antibody. * Muscle AChR content was determined by α-bungarotoxin binding to AChR present in Triton X-100 extracts from rat leg muscles, 48 h after Ig administrati The values ( mean±SEM) are averages derived from at least three different animals. EAMG was passively transferred in rats by mAb 198. The disease was induced within 24-48 h following administration of the antibody [Asher et al., 1993]. Muscle AChR content was determined by α-bungarotoxin binding to AChR present in Triton X-100 extracts from rat leg muscles, 48 h after the mAb administration. As previously reported, the myasthenic symptoms were accompanied by a marked reduction in the muscle AChR content (48% of normal control; Table 1). In order to examine the effect of the polypeptides of the invention on the disease symptoms, mAb 198 was preincubated with a 30 fold molar excess of recombinant polypeptides of the invention, or with either GST or BSA as controls, prior to its injection into rats. As shown in Table 1, the muscle AChR content in the EAMG-induced rats was reduced to 48% of AChR content of control untreated rats. The recombinant polypeptides of the invention were able to modulate in vivo muscle AChR loss and to decrease significantly clinical symptoms of EAMG. It was shown that preincubation of mAb 198 with Hαl-121+p3A prior to its injection into rats, prevented the appearance of myasthenic symptoms. The protected rats had a normal muscle AChR content (97% of control). Similar results were obtained with the Hαl-210+p3A polypeptide (data not shown). On the other hand, preincubation with either Hαl22-210+p3A or with GST or BSA did not affect the muscle AChR content significantly (61, 48 and 53% of control, respectively) and did not prevent myasthenic symptoms. Administration of Hαl-121+p3A and Hαl22-210+p3A alone did not induce any myasthenic symptoms in rats. Interestingly, similar protection effect by Hαl-121+p3A and Hαl-210+p3A was demonstrated when the recombinant polypeptide was injected together with mAb 198 without preincubation, or even two hours after the administration of mAb 198 (data not shown). Example 6: Protective effects of nasal administration of the polypeptides of the invention on actively induced EAMG in rats Hαl-210+p3A, Hαl-121+p3A and Hal 22-210 fused with GST were expressed and solubilized as described in Example 2. Nasal tolerance was induced in rats by administration of a daily dose of 2.5 μg of each of said fused polypeptides in 30 μl PBS into each rat nostril, over a period of ten consecutive days. Three days later the rats were immunized with Torpedo AChR (40 μg/rat) injected into the footpads, in Complete Freund's Adjuvant supplemented with 1 mg of Mycobacterium tuberculosis H37RA (DIFCO). Control rats received GST instead of the recombinant polypeptide. Clinical symptoms of EAMG disease, as well as body weight, were monitored weekly. The results of the experiment are summarized in Table 2, showing that all three tested polypeptides had a protective effect in the rats. Rats treated intranasally with either of the three recombinant fragments, before immunization with Torpedo AChR, were protected against EAMG, as assessed by clinical symptoms of EAMG as well as by weight loss and muscle AChR content as summarized in Table 2. 67%, 56% and 34% of the rats pretreated with Hαl-210+p3A, Hαl-121+p3A and Hαl22-210+p3A, respectively, were completely protected and did not develop clinical symptoms of EAMG, and the other rats in these groups were partially protected and had milder symptoms. On the other hand, all rats in the control, GST-pretreated group, were sick. As shown in Table 2, there was a marked effect of the treatment on the weight of the rats. Whereas rats in the control, GST-treated group, exhibited a notable decrease in body weight (12.8 + 9.2 g) characteristic to EAMG, between 3 weeks and 7 weeks following AChR injection, rats in groups pretreated with AChR fragments increased significantly in their body weight. The protective effect of the nasal treatment was also evident from the receptor content data. As seen in Table 2, there was a decrease of about 55% in AChR content in the control-GST treated rats, and only 1 1% decrease in AChR content in rats pretreated with Hαl-210+p3A. The recombinant fragments themselves had no myasthenogenic effects under the conditions employed for treatment. Protection against EAMG by nasal administration of the polypeptides of the invention was accompanied by a reduction in the proliferative T-cell response and IL-2 production in response to AChR (Fig. 9), and in the antibody titers to both Hαl-210+p3A and to self, rat AChR (Fig. 10). 27 RECTIFIED SHEET (RULE 91) ISA/EP Table 2: The effect of intranasal treatment with human recombinant AChR fragments on EAMG in rats. Clinical score a Healthy Δ weight AChR content Treatment 0 1 2 3 rats 3w to 7w 4 % & fmoles/mg % No/total prot. Control 0/10 2/10 2/10 4/10 0 -12.8±9.2 17.5±4.1 44 vehicle 2/10 (GST) Hal 22-210 3/9 3/9 1/9 1/9 1/9 33 +9.2±8.6 14.9±1.7 38 Hal-121 5/9 1/9 2/9 0/9 1/9 56 + 13.6±2.5 29.6±4.5 75 +p3A Hal-210 6/9 1/9 1/9 0/9 1/9 67 + 15.0±6.3 35.0±3.4 89 +p3A Normal rats 39.5±2.5 100 a Evaluated 7 weeks after the induction of EAMG. Example 7: Suppressive effects of nasal administration of the polypeptides of the invention on an ongoing EAMG. In order to evaluate the potential of the polypeptides of the invention to affect an ongoing disease, nasal administration of Hαl-210+p3A was initiated 7 days after the induction of EAMG by immunization with Torpedo AChR. At this time rats are known to be at the first, acute phase of EAMG. Other than the time of initiation, the protocol for the nasal administration was as in Example 6. As summarized in Table 3, suppression of EAMG was observed also when nasal treatment with Hαl-210+p3A was initiated after the induction of EAMG. Among the rats treated intranasally with Hαl-21+p3A, 30% were disease-free for at least 8 weeks following induction of EAMG, and in the other rats in the group the symptoms seemed to be milder. There was also an effect of the nasal treatment on the receptor content. As seen in Table 3, there was a loss of 68% in the AChR content in the control (treated intranasally with ovalbumin) rats, and only a 20% loss in the rats treated intranasally with Hαl-210+p3A. 29 RECTIFIED SHEET (RULE 91) Table 3: The effect of intranasal treatment with human recombinant AChR fragment Hal -210 +p3A on ongoing EAMG in rats. O o a Nasal administration was initiated 7 days after induction of EAMG by immunization with AChR and was continued for 12 consecutive days. bClinical evaluation was made 10 weeks after induction of EAMG. Example 8: Effects of oral administration of the polypeptides of the invention on EAMG in rats. The potential of oral administration of the polypeptides of the invention to prevent EAMG was first investigated. Two recombinant preparations of the extracellular domain of human AChR α-subunit were employed for oral tolerization: Hαl-210+p3A (fused with GST), and the extracellular domain itself (Hal -205+p3 A) expressed in the pET8C expression system with no fusion protein. Rats were fed 5 times with three days interval, each time with 0.6 mg of the recombinant fragment per rat, and AChR was injected in CFA to induce EAMG, three days after the last feeding. Rats were followed clinically, as well as for weight loss for 8 weeks after EAMG induction. As shown in Fig. 1 1, oral feeding with either GST-fused Hαl-210+p3A or with Hαl-205+p3A had a significant protective effect on the clinical symptoms of EAMG for at least 8 weeks. The values represent the average clinical score in the group at each time point. About 70% of the rats that were preatreated orally, did not develop any clinical symptoms and the other rats in this group were partially protected. The weight of the animals corroborated with the clinical evaluation. Control, nontreated rats, lost about 10 g per rat between 4 and 8 weeks after EAMG induction, whereas rats pretreated orally with the recombinant fragments gained about 10 g per rat during this time interval (Fig. 11). T-cell response to AChR as well as anti-rat AChR antibody titers were also reduced following oral treatment (Fig. 12). In the second part of the experiment, the potential of oral administration of Hαl-205+p3A to modulate an ongoing disease (in rats immunized with AChR) was investigated. In this experiment, a denatured preparation of Hαl-205+p3A (designated denHαl-215+p3A) was employed for oral treatment of sick rats. Denaturation of Hαl-205+p3A was performed in 6M guanidine HCL, followed by reduction with 0.1M β-mercaptoethanol and carboxymethylation with 0.15M iodoacetamide. Rats with a mild form of EAMG (clinical score of about 1) were pooled and divided randomly into two groups. Rats in the experimental group were fed 7 times with three days interval, each time with 0.3 mg of denHαl-205+p3A per rat, and rats in the control group were fed with ovalbumin. The rats were evaluated weekly for clinical symptoms and for their body weight. As seen in Fig. 13, the disease was arrested in the rats treated orally with the recombinant fragment and their body weight increased. On the other hand the disease progressed in rats of the control group and the rats lost weight gradually. 31 RECTIFIED SHEET (RULE 91) ISA/ These protection and suppression effects on EAMG shown in the above Examples, indicate that the polypeptides of the invention affect the autoimmune response to AChR in a manner that may be employed for immunotherapy of myasthenia gravis. Thus, the nasal or oral route of administration could provide a convenient therapeutic modality in humans. REFERENCES 1. Aharonov, A., Abramsky, O., Tarrab-Hazdai, R. and Fuchs, S. (1975). Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lancet 2: 340. 2. Asher, O., Neumann, D. and Fuchs, S. (1988). Increased levels of acetylcholine receptor α-subunit mRNA in experimental autoimmune myasthenia gravis. FEBS Lett 233: 277-81. 3. Asher, O., Kues, W. A., Witzemann, V., Tzartos, S. J., Fuchs, S. and Souroujon, M. C. (1993). 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Physiol. 489: 767-778. 22. Noda, M., Furutani, Y., Takahashi, H., Toyosato, M., Tanabe, T., Shimizu, S., Kikyotani, S., Kayano, T., Hirose, T., Inayama, S. and Numa, S. (1983). Cloning and sequence analysis of calf cDNA and human genomic DNA encoding α-subunit precursor of muscle acetylcholine receptor. Nature 305, 818-823. 23. Patrick, J. and Lindstrom, j. M. (1973). Autoimmune response to acetylcholine receptor. Science 180: 871-872. 24. Sambrook et al, eds. (1989) "Molecular Cloning: A Laboratory Manual", 2nd ed., Cold Spring Harbor Press. 25. Schoepfer, R., Luther, M. and Lindstrom, J. (1988). The human medulloblastoma cell line TE671 expresses a muscle-like acetylcholine receptor. Cloning of the alpha-subunit cDNA. FEBS Lett 226: 235-40. 26. Smith, D. B. and Johnson, K. S. (1988). Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67: 31-40. 27. Sophianos, D. and Tzartos, S.J. (1989). Fab fragments of monoclonal antibodies protect the human acetylcholine receptor against antigenic modulation caused by myasthenic sera. J. Autoimmunity 2, 777-789. 28. Souroujon, M.C., Pizzighella, S. Mochly-Rosen, D. and Fuchs, S. (1985). Antigenic specificity of acetylcholine receptor in developing muscle: Studies with monoclonal antibodies. J. of Neuroimmunology, 8; 159-166. 29. Souroujon, M. C, Pachner, A. R. and Fuchs, S. (1986). The treatment of passively transferred experimental myasthenia with anti- idiotypic antibodies. Neurology 36: 622-5. 30. Souroujon, M. C, Carmon, S. and Fuchs, S. (1992). Modulation of anti-acetylcholine receptor antibody specificities and of experimental autoimmune myasthenia gravis by synthetic peptides. Immunol Lett 34: 19-25. 31. Souroujon, M. C, Carmon, S. and Fuchs, S. (1993). Regulation of experimental autoimmune myasthenia gravis by synthetic peptides of the acetylcholine receptor. Ann N Y Acad Sci 681: 332-334. 32. Tzartos, S. and Lindstrom, J. (1980). Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc.Natl.Acad. Sci. USA 77: 755. 33. Tzartos, S. J., Hochschwender, S., Vasquez, P. and Lindstrom, J. (1987). Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor. J. Neuroimmunol. 15: 185-194. 34. Weiner, H. L., Friedman, A., Miller, A., Khoury, S. J., al, S. A., Santos, L., Sayegh, M., N, u. R., Trentham, D. E. and Hafler, D. A. (1994). Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol 12: 809-837. 35. Wilson, P. T., Lentz, T. L. and Hawrot, E. (1985). 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Claims: CLAIMS 1. A polypeptide capable of modulating the autoimmune response of an individual to acetylcholine receptor, said polypeptide being selected from the group consisting of: (i) a polypeptide corresponding to amino acid residues 1-210 of the human acetylcholine receptor (hAChR) α-subunit sequence depicted in Fig.l (Hal -210), in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2 (Hαl-210+p3A); (ii) a polypeptide corresponding to amino acid residues 1-205 of the hAChR α-subunit sequence depicted in Fig.l (Hal -210), in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2 (Hαl-205+p3A); (iii) a polypeptide corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l (Hal -121); (iv) a polypeptide corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l, in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α subunit gene, depicted in Fig. 2 (Hαl-121+p3A); (v) a polypeptide corresponding to amino acid residues 122-210 of the hAChR α-subunit sequence depicted in Fig.l (Hαl22-210); (vi) a polypeptide as in (i) to (v) or the polypeptide Hal -210 in which one or more amino acid residues have been added, deleted or substituted by other amino acid residues in a manner that the resulting polypeptide is capable of modulating the autoimmune response to acetylcholine receptor; (vii) a fragment of a polypeptide as in (i) to (vi), which fragment is capable of modulating the autoimmune response to acetylcholine receptor; (viii) a polypeptide comprising two or more fragments as in (vii) fused together with or without a spacer; (ix) a polypeptide or a fragment as defined in (i)-(viii) or the polypeptide Hal -210 fused to an additional polypeptide at its N- and/or C-terminal; and (x) soluble forms, denatured forms, chemical derivatives and salts of a polypeptide or a fragment as defined in (i)-(ix). 2. A polypeptide according to claim 1 corresponding to amino acid residues 1-210 of the hAChR α-subunit sequence depicted in Fig.1 , in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene depicted in Fig. 2. 3. A polypeptide according to claim 1 corresponding to amino acid residues 1-205 of the hAChR α-subunit sequence depicted in Fig.l, in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene depicted in Fig. 2. 4. A polypeptide according to claim 1, corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l . 5. A polypeptide according to claim 1, corresponding to amino acid residues 1-121 of the hAChR α-subunit sequence depicted in Fig.l, in which is inserted, between amino acid residues 58 and 59, a sequence of 25 amino acid residues encoded by the p3A exon of the hAChR α-subunit gene depicted in Fig.2. 6. A polypeptide according to claim 1, corresponding to amino acid residues 122-210 of the hAChR α-subunit sequence depicted in Fig.1. 7. A polypeptide or a fragment according 'to claim 1 (ix) wherein the additional polypeptide is glutathione S-transferase (GST) fused at the N-terminal of a polypeptide according to claim 1 (i) - (viii). 8. A DNA molecule coding for a polypeptide or a fragment according to claim 1. 9. A DNA molecule according to claim 8, being selected from the group consisting of: (i) a DNA molecule comprising the sequence of nucleotides 1 to 630, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2, is inserted between nucleotides 174 and 175; (ii) a DNA molecule comprising the sequence of nucleotides 1 to 615, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2, is inserted between nucleotides 174 and 175; (iii) a DNA molecule comprising the sequence of nucleotides 1 to 363 depicted in Fig.l; (iv) a DNA molecule comprising the sequence of nucleotides 1 to 363 depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2, is inserted between nucleotides 174 and 175; (v) a DNA molecule comprising the sequence of nucleotides 364 to 630 depicted in Fig.l; (vi) DNA molecules which are degenerate, as a result of the genetic code, to the DNA sequences of (i) to (v) and which code for a polypeptide coded for by any one of the DNA sequences of (i) to (v); (vii) a DNA molecule having a coding nucleotide sequence which is at least 70% homologous to any one of the DNA sequences of (i) to (vi) or to the DNA sequence coding for Hal -210; (viii) a DNA molecule as in (i) to (v) or the DNA molecule coding for Hal -210 in which one or more codons has been added, replaced or deleted in a manner that the polypeptide coded for by said sequence is capable of modulating the autoimmune response to acetylcholine receptor; (ix) a fragment of a DNA molecule as in (i)-(viii) which codes for a polypeptide capable of modulating the autoimmune response to acetylcholine receptor; (x) a DNA molecule comprising two or more fragments of (ix) fused together with or without a spacer, and which codes for a polypeptide capable of modulating the autoimmune response to acetylcholine receptor; and (xi) a DNA molecule comprising a nucleic acid sequence as defined in (i)-(x) or the DNA sequence coding for Hal -210 fused to additional coding DNA sequences at its 3' and or 5' end. 10. A DNA molecule according to claim 9 which comprises the sequence of nucleotides 1 to 630, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175, said DNA molecule coding for the polypeptide according to claim 2. 11. A DNA molecule according to claim 9 which comprises the sequence of nucleotides 1 to 615, depicted in Fig.l, in which the sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig.2, is inserted between nucleotides 174 and 175, said DNA molecule coding for the polypeptide according to claim 2. 12. A DNA molecule according to claim 9 which comprises the sequence of nucleotides 1 to 363 of the DNA sequence depicted in Fig.l, said DNA molecule coding for the polypeptide according to claim 3. 13. A DNA molecule according to claim 9 which comprises the sequence of nucleotides 1 to 363 of the DNA sequence depicted in Fig.l, in which a nucleic acid sequence of the p3A exon of the hAChR α-subunit gene, depicted in Fig. 2, is inserted between nucleotides 174 and 175, said DNA molecule coding for the polypeptide according to claim 4. 14. A DNA molecule according to claim 9 which comprises the sequence of nucleotides 364 to 630 of the DNA sequence depicted in Fig.l, said DNA molecule coding for the polypeptide according to claim 5. 15. A DNA molecule according to claim 9 (xi) wherein said additional nucleic acid sequence codes for glutathione S-transferase (GST) and is fused at the 5' end, said fused DNA molecule coding for a polypeptide according to claim 7. 16. A replicable expression vehicle comprising a DNA molecule according to any one of claims 8-15. 17. A prokaryotic or eukaryotic host cell transformed by a replicable expression vehicle of claim 16. 18. A process for preparing a polypeptide of any one of claims 1-7, comprising: (i) culturing a host cell of claim 17 under conditions promoting expression, and (ii) isolating the expressed polypeptide. 19. A process according to claim 17, wherein the expressed polypeptide is a fused polypeptide. 20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polypeptide selected from a polypeptide according to any one of claims 1 to 7 and a polypeptide comprising the amino acid residues 1-210 of the hAChR α-subunit depicted in Fig.l, soluble forms, denatured forms, salts and chemical derivatives thereof. 21. A pharmaceutical composition according to claim 20 for alleviation and/or treatment of myasthenia gravis. 22. A pharmaceutical composition according to claim 21 for nasal or oral administration. 23. A method for alleviation and/or treatment of myasthenia gravis which comprises administering to an individual in need thereof, an effective amount of a polypeptide according to any one of claims 1 to 7 or a polypeptide comprising the amino acid residues 1-210 of the hAChR α-subunit depicted in Fig.l, soluble forms, denatured forms, salts and chemical derivatives thereof. 24. A pharmaceutical composition according to claim 20 for diagnosis of myasthenia gravis. 25. A method for diagnosis of myasthenia gravis comprising: (i) incubating one or more polypeptides selected from a polypeptide according to any one of claims 1 to 7 and a polypeptide comprising the amino acid residues 1-210 of the hAChR α-subunit depicted in Fig.l, soluble forms, denatured forms, salts and chemical derivatives thereof, with a serum aliquote from an individual; and (ii) determining the amount of the anti-AChR antibodies in the serum bound to said polypeptide of (i); whereby detection of anti-AChR titers indicates the presence of myasthenia gravis.

Inventors: BARCHAN DORA, FUCHS SARA, SOUROUJON MIRIAM C, BARCHAN, DORA, FUCHS, SARA, SOUROUJON, MIRIAM, C.
Applicants: BARCHAN DORA, FUCHS SARA, SOUROUJON MIRIAM C, YEDA RES & DEV, BARCHAN, DORA, FUCHS, SARA, SOUROUJON, MIRIAM, C., YEDA RESEARCH AND DEVELOPMENT CO. LTD.
Application year: 1998
Main classification: C12N15
IPC codes: A61K38, C07K14, C12N1, C12N15