Production of subunits of soluble T cell receptors by co-transfe

Details Production of subunits of soluble T cell receptors by co-transfe Production of subunits of soluble T cell receptors by co-transfe

1994-09-14

1998-03-03

Jagannathan, Vasu S.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

435 4, 435 71, 435 6952, 435 697, 4351723, C12N 1512, C12N 1563, C12N 1579, C12N 1587

Patent

active

057233098

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to soluble T receptors and more particularly to secreted forms of soluble T receptors (sTR) V.alpha.C/.alpha./V.beta.C/.beta., V.gamma.C.gamma./V.delta.C.delta. or V.alpha.C.delta./V.beta.C/.gamma. and to their diagnostic and therapeutic applications.
2. Description of the Related Art
T lymphocytes are capable of recognizing, in a highly specific manner, myriads of antigens (Ag); this is by means of extremely diverse surface structures belonging to the superfamily of immunoglobulins (Ig), the T receptors (TR).
In man and in mice, most T lymphocytes in adults express sTR consisting of 2 variable glycoprotein sub-units called .alpha. and .beta.. Like the Ig heavy and light chains, these subunits contain an amino-terminal variable (V) domain and a carboxy-terminal constant (C) domain and are, in addition, very generally covalently associated with each other via an interchain disulphide bridge. The nature of the antigens recognized by the .alpha..beta. T receptor is relatively well established: they are complexes formed by an oligopeptide antigen (derived from the intracellular degradation of endogenous or exogenous proteins) closely associated with the polymorphic gene products situated in the so-called class I or II major histocompatibility complex (MHC). The interaction between the .alpha..beta. T receptor and the MHC/Ag complexes is conventionally reinforced by so-called coreceptor or accessory molecules (CD4 and CD8), which recognize conserved portions of the class II and I MHC molecules respectively.
Another subpopulation of T lymphocytes which can be distinguished by the nature of the genes (.gamma. and .delta.) encoding these T receptors has more recently been described. Contrary to the .alpha..beta. T lymphocytes, the antigenic specificity of the .gamma..delta. T cells still remains unclear. Based on the relative homology of the primary sequences of the .alpha..beta. and .gamma..delta. chains of the T receptor, some have predicted a structural similarity of the ligands for these receptors. In agreement with this hypothesis, a fraction of the .gamma..delta. T lymphocytes was found to be directed against molecules structurally similar or identical to the products of the MHC conventionally recognized by the .alpha..beta. T lymphocytes. However, there are also several examples of recognition by this T subpopulation of molecules of more distant structure, such as stress proteins or certain activating molecules such as CD48.
The present inventors have sought to generate "soluble" (secreted) forms of the .gamma..delta. T receptor, which could be used (like the Ig's) as probes permitting the isolation, localization and possibly the purification of specific ligands.
Moreover, such soluble T receptors also have a number of clinical applications. Traunecker et al. (1989. Inununol. Today 10:29) have reported attempts to produce soluble T receptors which consisted in removing the transmembrane (TM) portion of the .alpha. chains or .beta. chains by introducing a translational termination codon upstream of the sequences encoding the TM region which proved unsuccessful, no secretion having been detected.
Following these initial failures, other strategies were then adopted. In most cases, the principle consisted in constructing chimetic proteins comprising the V, or V and C regions of the .alpha. and .beta. subunits, joined to the C regions of immunoglobulins or to anchors of the glycosyl phosphatidylinositol (GPI) type. In the case of the TR/Ig fusion proteins, the main problem proved to be the sometimes predominant secretion of monomeric or homodimeric forms. In addition, the .alpha..beta. sTR heterodimeric forms sometimes exhibited significant structural differences with the membrane forms; in particular, the 2 .alpha. and .beta. chains were very generally non-covalently associated. This could consequently have effects on the overall structure and the fine antigenic specificity of such chimeric molecules. In the case of "lipidated"

REFERENCES:
patent: 5314995 (1994-05-01), Fell, Jr. et al.
"Heterodimeric, disulfide-linked alpha/bata T cell receptors in solution", uropean Journal of Immunology, vol. 21, No. 1, 1991, VCH Verlagsgesellschaft, Germany, by Alfred E. Slanetz et al., pp. 179-183.
"Engineered secreted T-cell receptor alpha beta heterodimers", Proceedings of the National Academy of Sciences of USA, vol. 88, No. 18, 1991, Washington by Claude Gregorie et al., pp. 8077-8081.
"A soluble, single-chain T-cell receptor arrangement endowed with antigen-combining properties", Proceedings of the National Academy of Sciences of USA, vol. 88, No. 19, 1991, Washington, by Jiri Novotny et al., pp. 8646-8650.
Sambrook et al. 1989, Molecular Cloning, pp. 15.51-15.52 Cold Spring Harbor Laboratory Press, NY.
Goverman et al. 1991, Basic & Clinical Immunol., ed. by Strites & Terr. Norwalk, CT, Appleton and Lange, pp. 73-77.
Chien et al. 1993, Immunology Today 14:597-602.

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