Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Glycoprotein – e.g. – mucins – proteoglycans – etc.
Reexamination Certificate
1996-07-18
2001-04-03
Nolan, Patrick J. (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Glycoprotein, e.g., mucins, proteoglycans, etc.
C530S402000, C530S807000
Reexamination Certificate
active
06211342
ABSTRACT:
BACKGROUND OF THE INVENTION
T cells mediate many immune responses, including transplant rejection, autoimmunity, viral infections, and tumor surveillance. T cell recognition of peptide antigens occurs via the T cell receptor (TCR) and requires that such antigen be presented to the TCR by a major histocompatibility complex (MHC) molecule, generally situated on the surface of an antigen presenting cell. The peptide antigen is held by the MHC molecule such that the T cell receptor recognizes the unique structure formed by the combination of the MHC molecule and the specific peptide. Thus, only a small percentage of T cell clones react to a given peptide.
There are two major known types of MHC molecules: class I and class II. MHC class I molecules are composed of an alpha chain with 3 domains (&agr;1, &agr;2, and &agr;3), as well as transmembrane and cytoplasmic domains. The &agr;1 and &agr;2 domains are polymorphic. A non-polymorphic protein, &bgr;2-microglobulin, self associates with the alpha chain and is necessary for stable conformation. MHC class I molecules are widely distributed and are present on most nucleated cells.
MHC class II molecules are composed of an alpha chain and a beta chain that self associate to form a heterodimer. Each chain has two extracellular domains (&agr;1, &agr;2 and &bgr;1, &bgr;2), as well as transmembrane and intracellular domains. The &agr;1 and &bgr;1 domains are polymorphic. MHC class II molecules are more restricted in distribution than are class I molecules.
Polymorphisms in the MHC molecules, as well as the wide spectrum of unique peptides that can associate with the MHC, result in an extremely diverse recognition pattern such that a given MHC-peptide combination is only recognized by a small percentage of T cell clones.
Present methods for modulating T cell function suffer from a number of limitations including lack of specificity. For example, therapies for suppressing T cell function (such as in autoimmunity or transplant rejection) cause generalized immunosuppression and may leave patients at risk for developing life-threatening infections. The ultimate goal of anti-T cell immunosuppressive therapy is to inhibit specific T cell alloreactive or autoreactive clones while leaving the majority of T cells fully functional. Specific immunosuppressive therapy requires targeting T cell clones recognizing specific MHC/peptide combinations. Several researchers have attempted to use soluble class I MHC molecules to inhibit allogenic T cell responses in vitro or in vivo. In general, soluble class I molecules have not effectively inhibited alloreactive T cell responses. Failure to observe inhibition of T cell function with soluble MHC may relate to the requirement for divalency to induce T cell anergy.
Present therapies for enhancing T cell function (such as in certain infections and malignancies) are often insufficient to induce an adequate immune response. Immunization with peptides alone has often not been successful at inducing a sufficient T cell response, since the peptide is quickly degraded by peptidases.
Several reports indicate that divalency of the MHC molecules is critical for signal delivery to the T cell, including both activating and inhibitory signals. Further, T cell priming requires stimulation via the TCR and an additional second signal generally delivered by an antigen presenting cell. In the absence of a second signal, T cell hyporesponsiveness results.
SUMMARY OF THE INVENTION
The present invention includes the process of creating a fusion protein that modulates T cell function in a peptide-specific manner, and the various methods by which the fusion protein modulates such function. The present invention is premised on the realization that a fusion protein which modulates specific T cell activity consists of three parts: (1) a plurality of MHC molecules; (2) a linker connecting the MHC molecules; and (3) a specific peptide or peptides loaded into the MHC molecules. In particular, the invention is directed to a fusion protein comprising a plurality of MHC molecules complexed to both a linker and to a selected peptide. The fusion protein targets the T cell receptor and modulates T cell function. Methods of stimulating, inhibiting or destroying T cells are provided by the fusion proteins. By constructing a fusion protein in which the linker allows delivery of a second signal, T cell stimulation results in enhanced T cell immunity. By constructing a fusion protein in which the linker does not provide for delivery of a second signal, T cell suppression results in immunosuppression. The fusion proteins can be delivered in vivo as superior therapeutic agents for T cell-mediated processes such as autoimmunity, infections, malignancies, and transplantation rejection.
REFERENCES:
patent: 5130297 (1992-07-01), Sharma et al.
patent: 5194425 (1993-03-01), Sharma et al.
patent: 5260422 (1993-11-01), Clark et al.
patent: 5284935 (1994-02-01), Clark et al.
patent: 5468481 (1995-11-01), Sharma et al.
patent: 5869270 (1999-02-01), Rhodes et al.
patent: WO 89/12459 (1989-12-01), None
patent: WO 93/10220 (1993-05-01), None
patent: WO 94/25054 (1994-11-01), None
patent: WO 95/23814 (1995-09-01), None
Kumar et al., P.N.A.S USA, vol. 87:1337-1341, Feb. 1990.*
Konig et al., J. Exp. Medicine, vol. 182: 779-787, Sep. 1995.*
Harding et al., J. Exp. Medicine, vol. 177: 1791-1796, Jun. 1993.*
Roit et al., Immunology, C.V. Mosby, Publishers, St.Louis, Jan. 1986, p. 5.3.*
“Expression and characterization of a class I MHC immunoglobulin heavy chain fusion protein.” Cullen et al.:Abstract No. 2770, p. 468 9th International Congress of immunology, San Francisco, Jul. 1995.
Dal Porto, J. et al. “A soluble divalent class I major histocompatibility complex molecule inhibits alloreactive T cells at nanomolar concentrations.”Proc. Natl. Acad. Sci. USA(1993) vol. 90, pp. 6671-75.
Buelow, R. et al. “Immunomodulation by Soluble HLA Class I.”Transplantation(1995) vol. 59, pp. 649-54.
Nicolle, M. W. et al. “Specific Tolerance to an Acetylcholine Receptor Epitope Induced In Vitro in Myasthenia Gravis CD4+Lymphocytes by Soluble Major Histocompatibility Complex Class II-Peptide Complexes.”J. Clin. Invest.(1994) vol. 93, pp. 1361-69.
Kozono, H. et al. “Production of soluble MHC class II proteins with covalently bound single peptides.”Nature(1994) vol. 369, pp. 151-54.
Abastado, J-P. et al. “A soluble, single-chain Kdmolecule produced by yeast selects a peptide repertoire indistinguishable from that of cell-surface-associated Kd.”Eur. J. Immunol.(1993) vol. 23, pp. 1776-783.
Williams, M.E. et al. “Antigen Receptor-Mediated Anergy In Resting T Lymphocytes And T Cell Clones.”J. Immunol.(1992) vol. 149, pp. 1921-26.
Mage, M.G. et al. “A recombinant, soluble, single-chain class I major histocompatibility complex molecule with biological activity.”Proc. Natl. Acad. Sci, USA(1992) vol. 89, pp. 10658-662.
Arnold, B. et al. “Transgenic mice expressing a soluble foreign H-2 class I antigen are tolerant to allogeneic fragments presentedby self class I but not to the whole membrane-bound alloantigen.”Proc. Natl. Acad. Sci. USA(1990) vol. 87, pp. 1762-66.
Schneck, J. et al. “Inhibition of an Allospecific T Cell Hybridoma by Soluble Class I Proteins and Peptides: Estimation of the Affinity of a T Cell Receptor for MHC.”Cell(1989) vol. 56, pp. 47-55.
Arnold, B. et al. “Allorective immune responses of transgenic mice expressing a foreign transplantation antigen in a soluble form.”Proc. Natl. Acad. Sci. USA(1988) vol. 85, pp. 2269-273.
McCluskey, J. et al. “T Cell Activation By Purified, Soluble, Class I MHC Molecules.”J. Immunol.(1988) vol. 141, pp. 1451-55.
Herrmann, S. H. and Mescher, M.F. “The Requirements for Antigen Multivalency In Class I Antigen Recognition and Triggering of Primed Precursor Cytolytic T Lymphocytes.”J. Immunol.(1986) vol. 136, No. 8, pp. 2816-25.
Herrmann, S.H. and Mescher, M. F., “Secondary cytolytic T lymphocytes stimulation by purified H-2Kkin liposomes.”Proc. Natl. Acad. Sci. U.SA(1981) vol. 78, pp. 2488-92.
Cullen Constance M.
Hirsch Raphael
Children's Hospital Medical Center
Knobbe Martens Olsen & Bear LLP
Nolan Patrick J.
LandOfFree
Multivalent MHC complex peptide fusion protein complex for... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Multivalent MHC complex peptide fusion protein complex for..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Multivalent MHC complex peptide fusion protein complex for... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2435305