Soluble polypeptide fractions of the LAG-3 protein, production m

Details Soluble polypeptide fractions of the LAG-3 protein, production m Soluble polypeptide fractions of the LAG-3 protein, production m

1996-12-24

1999-09-21

Saunders, David

Chemistry: molecular biology and microbiology

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

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

435455, 530324, 530330, 530350, 5303913, 5303917, C12P 2100, C12N 1509, A61K 3807, A61K 3816

Patent

active

059553006

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to soluble forms derived from the LAG-3 membrane protein which are useful as immunosuppressants, as well as antibodies capable of preventing the specific binding of the LAG-3 protein to MHC (major histocompatibility complex) Class II molecules as immunostimulants.
2. Description of the Related Art
In WO-A 91/10682, a protein designated LAG-3 has been described.
The LAG-3 protein is a protein selectively expressed by NK cells and activated T lymphocytes. Similarity of the amino acid sequence, the comparative exon/intron organization and the chromosomal localization show that LAG-3 is related to CD4. The initial characterization of the LAG-3 gene has been described by TRIEBEL et al. (1).
The corresponding DNA codes for a type I transmembrane protein of 498 amino acids containing 4 extra-cellular sequences of the immunoglobulin type. LAG-3 is a member of the immunoglobulin superfamily.
The mature protein comprises 476 amino acids (SEQ ID No. 1) with a theoretical molecular weight of 52 kD. The extracellular region contains 8 cysteine residues and 4 potential N-glycosylation sites. By Western blot analysis, it was shown that LAG-3 inside PRA-blasts or activated NK cells has an apparent mass Mr of 70,000. After treatment with N-glycosidase F, a reduction in size to 60 kD was obtained, thereby demonstrating that native LAG-3 is glycosylated. Fuller details are described in WO-A 91/10682.
BAIXERAS et al., in J. Exp. Med. 176, 327-337 (2), have, in addition, described their finding that rosette formation between cells transfected with LAG-3 (expressing LAG-3 at their surface) and B lymphocytes expressing MHC Class II was specifically dependent on LAG-3/MHC Class II interaction.
Surprisingly, this ligand for MHC Class II was detected with higher levels on activated CD8.sup.+ lymphocytes (MHC Class I-restricted) than on activated CD4.sup.+ lymphocytes. In vivo, only a few disseminated LAG-3.sup.+ cells (MHC Class II-restricted) were to be found in non-hyperplastic lymphoid tissue comprising the primary lymphoid organs, that is to say thymus and bone marrow. LAG-3.sup.+ cells were to be found in hyperplastic lymphoid nodules and tonsils, as well as among peripheral blood mononuclear cells (PBMC) of patients receiving injections of high doses of IL-2.
These observations confirm that LAG-3 is an activation antigen in contrast to CD4 expressed in a subpopulation of resting lymphocytes and other cell types, in particular macrophages.
The MHC comprises Class I and Class II molecules which are membrane glycoproteins which present fragments of protein antigens to the T lymphocyte receptors (TCR). Class I molecules are responsible for the presentation to CD8.sup.+ cytotoxic cells of peptides derived in large part from endogenously synthesized proteins, while Class II molecules present to CD4.sup.+ helper lymphocytes peptides originating in the first place from foreign proteins which have entered the endocytic, that is to say exogenous, pathway. T helper lymphocytes regulate and amplify the immune response, while cytotoxic lymphocytes are needed to destroy cells irrespective of the tissues expressing "non-self" antigens, for example viral antigens. The mechanism of recognition involves intracellular signals leading to an effective activity of T lymphocytes.
It is apparent that, to initiate an immune response mediated by T (CD4.sup.+) lymphocytes, the foreign antigens must be captured and internalized in the form of peptides by specialized cells, the antigen presenting cells (APC). The resulting antigenic peptides are reexpressed at the surface of the antigen presenting cells, where they are combined with MHC Class II molecules. This MHC Class I/peptide complex is specifically recognized by the T lymphocyte receptor, resulting in an activation of the T helper lymphocytes.
Moreover, animal models created by recombination techniques have made it possible to emphasize the part played in vivo by MHC Class II molecules and their ligands.
Thus, mice deficie

REFERENCES:
Elena Biaxeras et al., "Characterization of the Lymphocyte Activation Gene -Encoded Protein. A New Ligand for Human Leukocyte Antigen Class II Antigens", The Journal of Experimental Medicine, vol. 176, No. 2, Aug. 1992, New York, pp. 327-337.
Frederic Triebel et al., "LAG-3, a Novel Lymphocyte Activation Gene Closely Related to CD4", The Journal of Experimental Medicine, vol. 171, No. 5, May 1990, New York, pp. 1393-1405.
Bertrand Huard et al., "The Lymphocyte Activation Gene Product LAG-3 is a Ligand for Class II Antigens", 8 International Congress of Immunology. Abstracts, Aug. 1992, Budapest, p. 281.
B. Huard et al., "Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand", Immunogenetics, vol. 39, No. 3, Mar. 1994, New York, pp. 213-217.
Eilat, D et al. Proc. Natl. Acad. Sci. (USA). 89(15):6871-6875, Aug. 1, 1992.
De Santes, K et al. Cancer Research. 52:1916-1923, Apr. 1, 1992.
Taetle, R. et al. J. Natl. Cancer Inst. 80(13):1053-1059, Sep. 7, 1988.

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