Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1995-06-07
2002-06-18
Eyler, Yvonne (Department: 1646)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S069100, C435S069700, C435S320100, C435S325000, C435S006120, C435S235100, C530S300000, C530S350000, C536S023100, C536S023530, C536S023520
Reexamination Certificate
active
06407221
ABSTRACT:
INTRODUCTION
1. Technical Field
The field of this invention is the use of chimeric surface membrane proteins for signal transduction.
2. Background
Regulation of cell activities is frequently achieved by the binding of the ligand to a surface membrane receptor. The formation of the complex with the extracellular portion of the receptor results in a change in conformation with the cytoplasmic portion of the receptor undergoing a change which results in a signal being transduced in the cell. In some instances, the change in the cytoplasmic portion results in binding to other proteins, where the other proteins are activated and may carry out various functions. In some situations, the cytoplasmic portion is autophosphorylated or phosphorylated, resulting in a change in its activity. These events are frequently coupled with secondary messengers, such as calcium, cyclic adenosine monophosphate, inositol phosphate, diacylglycerol, and the like. The binding of the ligand results in a particular signal being induced.
There are a number of instances, where one might wish to have a signal induced by virtue of employing a different ligand. For example, one might wish to activate particular T-cells, where the T-cells will then be effective as cytotoxic agents, or activating agents by secretion of interleukins, colony stimulating factors or other cytokines, which results in the stimulation of another cell. The ability of the T-cell receptor to recognize antigen is restricted by the nature of Major Histocompatibility Complex (MHC) antigens on the surface of the host cell. Thus, the use of a chimeric T-cell receptor in which a non-MHC restricted ligand binding domain is linked directly to the signal transducing domain of the T-cell receptor would permit the use of the resulting engineered effector T-cell in any individual, regardless of their MHC genetic background. In this manner, one may change the ligand which initiates the desired response, where for some reason, the natural agent may not be as useful.
There is, therefore, interest in finding ways to modulate cellular responses in providing for the use of ligands other than the normal ligand to transduce a desired signal.
Relevant Literature
The T-cell antigen receptor (TCR) has a non-covalent association between a heterodimer, the antigen/MHC binding subunit Ti variable component and the five invariant chains: zeta (&zgr;), eta (&eegr;) and the three CD3 chains: gamma (&ggr;), delta (&dgr;) and epsilon (&egr;) (Weiss and Imboden (1987)
Adv. Immunol
., 41:1-38; Cleavers et al. (1988)
Ann. Rev. Immunol
., 6:629-662; Frank et al. (1990)
Sem. Immunol
., 2:89-97). In contrast to the Ti alpha/beta heterodimer which is solely responsible for antigen binding, the physically associated CD3-zeta/eta complex does not bind ligand, but is thought to undergo structural alterations as a consequence of Ti-antigen interaction which results in activation of intracellular signal transduction mechanisms.
A description of the zeta chain may be found in Ashwell and Klausner (1990)
Ann. Rev. Immunol
., 8:139-167. The nature of the zeta chain in the TCR complex is described by Baniyash et al. (1988)
J. Biol. Chem
., 263:9874-9878 and Orloff et al. (1989) ibid., 264:14812-14817. The heterodimeric zeta and eta protein is described by Jin et al. (1990)
Proc. Natl. Acad. Sci. USA
, 87:3319-3323. Discussion of the homo- and heterodimers may be found in Mercep et al. (1988)
Science
, 242:571-574; and Mercep et al. (1989) ibid., 246:1162-1165. See also Sussman et al. (1988)
Cell
, 52:85-95. For studies of the role of the zeta protein, see Weissman et al. (1989)
EMBO, J
., 8:3651-3656; Frank et al. (1990)
Science
, 249:174-177; and Lanier et al. (1989)
Nature
, 342:803-805.
For discussion of the gamma subunit of the Fc
&egr;
R1 receptor, expressed on mast cells and basophils and its homology to the zeta chain, see Bevan and Cunha-Melo (1988)
Prog. Allergy
, 42:123-184; Kinet (1989)
Cell
, 57:351-354; Benhamou et al.,
Proc. Natl. Acad. Sci. USA
, 87:5327-5330; and Orloff et al. (1990)
Nature
, 347:189-191.
The zeta(&zgr;) chain is structurally unrelated to the three CD3 chains, and exists primarily as a disulfide-linked homodimer, or as a heterodimer with an alternatively spliced product of the same gene, eta (&eegr;). The zeta chain is also expressed on natural killer cells as part of the Fc&ggr;RIII receptor. The gamma chain of the Fc&egr; receptor is closely related to zeta, and is associated with the Fc&egr;RI receptor of mast cells and basophils and the C16 receptor expressed by macrophages and natural killer cells. The role in signal transduction played by the cytoplasmic domains of the zeta and eta chains, and the gamma subunit of the FcRI receptor has been described by Irving and Weiss (1991)
Cell
64:891-901; Romeo and Seed, (1991)
Cell
64:1037-1046 and Letourneur and Klausner (1991)
Proc. Natl. Acad. Sci. USA
88:8905-8909. More recent studies have identified an 18 amino-acid motif in the zeta cytoplasmic domain that, upon addition to the cytoplasmic domain of unrelated transmembrane proteins, endows them with the capacity to initiate signal transduction (Romeo et al. (1992)
Cell
68:889-897). These data suggest a T cell activation mechanism in which this region of zeta interacts with one or more intracellular proteins.
The three CD3 chains, gamma (&ggr;), delta (&dgr;) and epsilon (&egr;), are structurally related polypeptides and were originally implicated in signal transduction of T cells by studies in which anti-CD3 monoclonal antibodies were shown to mimic the function of antigen in activating T cells (Goldsmith and Weiss (1987)
Proc. Natl. Acad. Sci. USA
84:6879-6883), and from experiments employing somatic cell mutants bearing defects in TCR-mediated signal transduction function (Sussman et al. (1988)
Cell
52:85-95). Sequences similar to the active motif found in zeta are also present in the cytoplasmic domains of the CD3 chains gamma and delta. Chimeric receptors in which the cytoplasmic domain of an unrelated receptor has been replaced by that of CD3 epsilon have been shown to be proficient in signal transduction (Letourneur and Klausner (1992)
Science
255:79-82), and a 22 amino acid sequence in the cytoplasmic tail of CD3 epsilon was identified as the sequence responsible. Although the cytoplasmic domains of both zeta and CD3 epsilon have been shown to be sufficient for signal transduction, quantitatively distinct patterns of tyrosine phosphorylation were observed with these two chains, suggesting that they may be involved in similar but distinct biochemical pathways in the cell.
The phosphatidylinositol-specific phospholipase C initiated activation by the T-cell receptor (“TCR”) is described by Weiss et al. (1984)
Proc. Natl. Acad, Sci. USA
, 81:416-4173; and Imboden and Stobo (1985)
J. Exp. Med
., 161:446-456. TCR also activates a tyrosine kinase (Samelson et al. (1986)
Cell
, 46:1083-1090; Patel et al. (1987)
J. Biol. Chem
., 262:5831-5838; Chsi et al. (1989)
J. Biol. Chem
., 264:10836-10842, where the zeta chain is one of the substrates of the kinase pathway (Baniyash et al. (1988)
J. Biol. Chem
., 263:18225-18230; Samelson et al. (1986), supra). Fyn, a member of the src family of tyrosine kinases, is reported to coprecipitate with the CD3 complex, making it an excellent candidate for a TCR-activated kinase (Samelson et al. (1990)
Proc. Natl. Acad. Sci. USA
, 87:4358-4362). In addition, a tyrosine kinase unrelated to fyn has been shown to interact with the cytoplasmic domain of zeta (Chan et al., (1991)
Proc. Natl. Acad. Sci. USA
, 88:9166-9170).
Letourner and Klausner (1991)
Proc. Natl. Acad. Sci. USA
88: 8905-8909 describe activation of T cells using a chimeric receptor consisting of the extracellular domains of the &agr; chain of the human interleukin 2 receptor (Tac) and the cytoplasmic domain of either &zgr; or &ggr;. Gross et al., (1989)
Proc. Natl. Acad. Sci. USA
86: 10024-10028 describe activation of T cells using chimeric receptors in which the MHC-restricted antigen-binding domains of the T cell r
Capon Daniel J.
Irving Brian A.
Roberts Margo R.
Weiss Arthur
Zsebo Krisztina
Basi Nirmac S.
Cell Genesys Inc.
Eyler Yvonne
Roylance Abrams Berdo & Goodman L.L.P.
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