Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-01-08
2002-09-03
Huff, Sheela (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C424S134100
Reexamination Certificate
active
06444792
ABSTRACT:
BACKGROUND OF THE INVENTION
To induce antigen-specific T cell activation and clonal expansion, two signals provided by antigen-presenting cells (APCs) must be delivered to the surface of resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987)
J. Exp. Med
. 165:302-319; Mueller, D. L., et al. (1990)
J. Immunol
. 144:3701-3709; Williams, I. R. and Unanue, E. R. (1990)
J. Immunol
. 145:85-93). The first signal, which confers specificity to the immune response, is mediated via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Schwartz, R. H. (1990)
Science
248:1349-1356). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface molecules expressed by APCs (Jenkins, M. K., et al. (1988)
J. Immunol
. 140:3324-3330; Linsley, P. S., et al. (1991)
J. Exp. Med
. 173:721-730; Gimmi, C. D., et al., (1991)
Proc. Natl. Acad. Sci. USA
. 88:6575-6579; Young, J. W., et al. (1992)
J. Clin. Invest
. 90:229-237; Koulova, L., et al. (1991)
J. Exp. Med
. 173:759-762; Reiser, H., et al. (1992)
Proc. Natl. Acad. Sci. USA
. 89:271-275; van-Seventer, G. A., et al. (1990)
J. Immunol
. 144:4579-4586; LaSalle, J. M., et al., (1991)
J. Immunol
. 147:774-80; Dustin, M. I., et al., (1989)
J. Exp. Med
. 169:503; Armitage, R. J., et al. (1992)
Nature
357:80-82; Liu, Y., et al. (1992)
J. Exp. Med
. 175:437-445).
Considerable evidence suggests that the B7-1 protein (CD80; originally termed B7), expressed on APCs, is one such critical costimulatory molecule (Linsley, P. S., et al., (1991)
J. Exp. Med
. 173:721-730; Gimmi, C. D., et al., (1991)
Proc. Natl. Acad Sci. USA
. 88:6575-6579; Koulova, L., et al., (1991)
J. Exp. Med
. 173:759-762; Reiser, H., et al. (1992)
Proc. Natl. Acad Sci. USA
. 89:271-275; Linsley, P. S. et al. (1990)
Proc. Natl. Acad. Sci. USA
. 87: 5031-5035; Freeman, G. J. et al. (1991)
J. Exp. Med
. 174:625-631.). Recent evidence suggests the presence of additional costimulatory molecules on the surface of activated B lymphocytes (Boussiotis V. A., et al. (1993)
Proc. Natl. Acad Sci. USA
, 90:11059-11063; Freeman G. J., et al. (1993)
Science
262:907-909; Freeman G. J., et al. (1993)
Science
262:909-911; and Hathcock K. S., et al. (1993)
Science
262:905-907). The human B lymphocyte antigen B7-2 (CD86) has been cloned and is expressed by human B cells at about 24 hours following stimulation with either anti-immunoglobulin or anti-MHC class II monoclonal antibody (Freeman G. J., et al. (1993)
Science
262:909-911). At about 48 to 72 hours post activation, human B cells express both B7-1 and a third CTLA4 counter-receptor which is identified by a monoclonal antibody BB-1, which also binds B7-1 (Yokochi, T., et al. (1982)
J. Immunol
. 128:823-827). The BB-1 antigen is also expressed on B7-l negative activated B cells and can costimulate T cell proliferation without detectable IL-2 production, indicating that the B7-1 and BB-1 molecules are distinct (Boussiotis V. A., et al. (1993)
Proc. Natl. Acad Sci. USA
90:11059-11063). The presence of these costimulatory molecules on the surface of activated B lymphocytes indicates that T cell costimulation is regulated, in part, by the temporal expression of these molecules following B cell activation.
B7-1 is a counter-receptor for two ligands expressed on T lymphocytes. The first ligand, termed CD28, is constitutively expressed on resting T cells and increases after activation. After signaling through the T cell receptor, ligation of CD28 induces T cells to proliferate and secrete IL-2 (Linsley, P.S., et al. (1991)
J. Exp. Med
. 173: 721-730; Gimmi, C. D., et al. (1991)
Proc. Natl. Acad. Sci. USA
. 88:6575-6579; Thompson, C. B., et al. (1989)
Proc. Natl. Acad. Sci. USA
. 86:1333-1337; June, C. H., et al. (1990)
Immunol. Today
. 11:211-6; Harding, F. A., et al. (1992)
Nature
. 356:607-609.). The second ligand, termed CTLA4, is homologous to CD28, but is not expressed on resting T cells and appears following T cell activation (Brunet, J. F., et al., (1987)
Nature
328:267-270). Like B7-1, B7-2 is a counter-receptor for both CD28 and CTLA4 (Freeman G. J., et al. (1993)
Science
262:909-911). CTLA4 was first identified as a mouse cDNA clone, in a library of cDNA from a cytotoxic T cell clone subtracted with RNA from a B cell lymphoma (Brunet, J. F., et al. (1987) supra). The mouse CTLA4 cDNA was then used as a probe to identify the human and mouse CTLA4 genes (Harper, K., et al. (1991)
J. Immunol
. 147:1037-1044; and Dariavich, et al. (1988)
Eur. J. Immunol
. 18(12):1901-1905, sequence modified by Linsley, P. S., et al. (1991)
J. Exp. Med
. 174:561-569). A probe from the V domain of the human gene was used to detect the human cDNA which allowed the identification of the CTLA4 leader sequence (Harper, K., et al. (1991) supra).
Soluble derivatives of cell surface glycoproteins in the immunoglobulin gene superfamily have been made consisting of an extracellular domain of the cell surface glycoprotein fused to an immunoglobulin constant (Fc) region (see e.g., Capon, D. J. et al. (1989)
Nature
337:525-531 and Capon U.S. Pat. Nos. 5,116,964 and 5,428,130 [CD4-IgG1 constructs]; Linsley, P. S. et al. (1991)
J. Exp. Med
. 173:721-730 [a CD28-IgG1 construct and a B7-1-IgG1 construct]; and Linsley, P. S. et al. (1991)
J. Exp. Med
. 174:561-569 and U.S. Pat. No. 5,434,131 [a CTLA4-IgG1). Such fusion proteins have proven useful for studying receptor-ligand interactions. For example, a CTLA4-IgG immunoglobulin fusion protein was used to study interactions between CTLA4 and its natural ligands (Linsley, P. S., et al., (1991)
J. Exp. Med
. 174:561-569; International Application WO93/00431; and Freeman G. J., et al. (1993)
Science
262:909-911).
The importance of the B7: CD28/CTLA4 costimulatory pathway has been demonstrated in vitro and in several in vivo model systems. Blockade of this costimulatory pathway results in the development of antigen specific tolerance in murine and human systems (Harding, F. A., et al. (1992)
Nature
356:607-609; Lenschow, D. J., et al. (1992)
Science
257:789-792; Turka, L. A., et al. (1992)
Proc. Natl. Acad. Sci. USA
89:11102-11105; Gimmi, C. D., et al. (1993)
Proc. Natl. Acad. Sci. USA
90:6586-6590; Boussiotis, V., et al. (1993)
J. Exp. Med
. 178:1753-1763). Conversely, transfection of a B7-1 gene into B7-1 negative murine tumor cells to thereby express B7-1 protein on the tumor cell surface induces T-cell mediated specific immunity accompanied by tumor rejection and long lasting protection to tumor challenge (Chen, L., et al. (1992)
Cell
71: 1093-1102; Townsend, S. E. and Allison, J. P. (1993)
Science
259:368-370; Baskar, S., et al. (1993)
Proc. Nati. Acad. Sci. USA
90:5687-5690.). Therefore, approaches which manipulate the B7: CD28/CTLA4 interaction to thereby stimulate or suppress immune responses would be beneficial therapeutically.
SUMMARY OF THE INVENTION
This invention pertains to CTLA4-immunoglobulin fusion proteins having modified immunoglobulin constant (IgC) region-mediated effector functions and to nucleic acids encoding the proteins. In one embodiment, the fusion proteins of the present invention have been constructed by fusing a peptide having a CTLA4 activity and a second peptide comprising an immunoglobulin constant region to create a CTLA4Ig fusion protein. In another embodiment, the variable regions of immunoglobulin heavy and light chains have been replaced by the B7-binding extracellular domain of CTLA4 to create CTLA4-Ab fusion proteins. As used herein, the term “CTLA4-immunoglobulin fusion protein” refers to both the CTLA4Ig and CTLA4-Ab forms. In a preferred embodiment, the fusion proteins of the invention have been modified to reduce their ability to activate complement and/or bind to Fc receptors. In one embodiment, an IgC region of an isotype other than C&ggr;1 is used i
Carson Jerry
Gray Gary S.
Javaherian Kashi
Rennert Paul D.
Silver Sandra
Helms Larry R.
Huff Sheela
Lahive & Cockfiled, LLP
Mandragouras Esq. Amy E.
Repligen Corporation
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