Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1997-08-19
2001-03-06
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S193100
Reexamination Certificate
active
06197302
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.
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Cullen Constance M.
Hirsch Raphael
Children's Hospital Medical Center
Knobbe Martens Olsen & Bear LLP
Nolan Patrick J.
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