Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1994-03-02
2001-04-17
Gambel, Phillip (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C530S325000, C530S324000, C530S323000, C536S023100, C536S023400, C536S023500
Reexamination Certificate
active
06218510
ABSTRACT:
BACKGROUND OF THE INVENTION
For CD4+ T lymphocyte activation to occur, two distinct signals must be delivered by antigen presenting cells to resting T lymphocytes (Schwartz, R. H. (1990)
Science
248:1349-1356; Williams, I. R. and Unanue, E. R. (1991)
J. Immunol.
147:3752-3760; Mueller, D. L. et al., (1989)
J. Immunol.
142:2617-2628). The first, or primary, activation signal is mediated physiologically by the interaction of the T cell receptor/CD3 complex (TcR/CD3) with MHC class II-associated antigenic peptide and gives specificity to the immune response. The second signal, the costimulatory signal, regulates the T cell proliferative response and induction of effector functions. Costimulatory signals appear pivotal in determining the functional outcome of T cell activation since delivery of an antigen-specific signal to a T cell in the absence of a costimulatory signal results in functional inactivation of mature T cells, leading to a state of tolerance (Schwartz, R. H. (1990)
Science
248:1349-1356).
Molecules present on the surface of antigen presenting cells which are involved in T cell costimulation have been identified. These T cell costimulatory molecules include murine B
7
-
1
(mB
7
-
1
; Freeman, G. J. et al., (1991)
J. Exp. Med.
174:625-631), and the more recently identified murine B
7
-
2
(mB
7
-
2
; Freeman, G. J. et al., (1993)
J. Exp. Med.
178:2185-2192). Human counterparts to the murine B
7
-
1
and B
7
-
2
molecules have also been described (human B
7
-
1
(hB
7
-
1
) Freedman, A.S. et al., (1987)
J. Immunol.
137:3260-3267; Freeman, G. J. et al., (1989)
J. Immunol.
143:2714-2722; and human B
7
-
2
(hB
7
-
2
); Freeman, G. J. et al., (1993)
Science
262:909-911; Azuma, M. et al. (1993)
Nature
366:76-79). The B
7
-
1
and B
7
-
2
genes are members of the immmunoglobulin gene superfamily.
B
7
-
1
and B
7
-
2
display a restricted pattern of cellular expression, which correlates with accessory cell potency in providing costimulation (Reiser, H. et al. (1992;
Proc. Natl. Acad. Sci. USA
89:271-275; Razi-Wolf Z. et al., (1992)
Proc. Natl. Acad. Sci. USA
89:4210-4214; Galvin, F. et al. (1992)
J. Immunol.
142:3802-3808; Freeman, G. J. et al., (1993)
J. Exp. Med
178:2185-2192). For example, B
7
-
1
has been observed to be expressed on activated B cells, T cells and monocytes but not on resting B cells, T cells or monocytes, and its expression can be regulated by different extracellular stimuli (Linsley, P. S. et al., (1990)
Proc. Natl.Acad. Sci. USA
87:5031-5035; Linsley, P. S. et al., (1991)
J. Exp. Med.
174:561-569; Reiser, H. et al. (1992);
Proc. Natl. Acad. Sci. USA
89:271-275; 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; Azuma, M. et al. (1993)
J. Exp. Med.
177:845-850; Sansom, D. M. et al. (1993)
Eur. J. Immunol.
23:295-298)
Both B
7
-
1
and B
7
-
2
are counter-receptors for two ligands, CD
28
and CTLA
4
, expressed on T lymphocytes (Linsley, P. S. et al., (1990)
Proc. Natl.Acad. Sci. USA
87:5031-5035; Linsley, P. S. et al., (1991)
J. Exp. Med.
174:561-569). CD
28
is constitutively expressed on T cells and, after ligation by a costimulatory molecule, induces IL-
2
secretion and T cell proliferation (June, C. H. et al. (1990)
Immunol. Today
11:211-216). CTLA
4
is homologous to CD
28
and appears on T cells after activation (Freeman, G. J. et al. (1992)
J. Immunol.
149:3795-3801). Although CTLA
4
has a significantly higher affinity for B
7
-
1
than does CD
28
, its role in T cell activation remains to be determined. It has been shown that antigen presentation to T cells in the absence of the B
7
-
1
/CD
28
costimulatory signal results in T cell anergy (Gimmi, C. D. et al. (1993)
Proc. Natl. Acad. Sci. USA
90:6586-6590; Boussiotis, V. A. et al. (1993)
J. Exp. Med.
178:1753). The ability of T cell costimulatory molecules such as B
7
-
1
and B
7
-
2
to bind to CD
28
and/or CTLA
4
on T cells and trigger a costimulatory signal in the T cells provides a functional role for these molecules in T cell activation.
SUMMARY OF THE INVENTION
This invention pertains to novel forms of T cell costimulatory molecules. In particular, the invention pertains to isolated proteins encoded by T cell costimulatory molecule genes which contain amino acid sequences encoded by novel exons of these genes. The isolated proteins of the invention correspond to alternative forms of T cell costimulatory molecules. Preferably, these alternative forms correspond to naturally-occurring, alternatively spliced forms of T cell costimulatory molecules or are variants of alternatively spliced forms which are produced by recombinant DNA techniques. The novel forms of T cell costimulatory molecules of the invention contain an alternative structural domain (i.e., a structural domain having an amino acid sequence which differs from a known amino acid sequence) or have a structural domain deleted or added. The occurrence in nature of alternative structural forms of T cell costimulatory molecules supports additional functional roles for T cell costimulatory molecules.
The invention also provides isolated nucleic acid molecules encoding alternative forms of proteins which bind to CD
28
and/or CTLA
4
and isolated proteins encoded therein. Isolated nucleic acid molecules encoding polypeptides corresponding to novel structural domains of T cell costimulatory molecules, and isolated polypeptide encoded therein are also within the scope of the invention. The novel structural domains of the invention are encoded by exons of T cell costimulatory molecule genes. In one embodiment of the invention, the T cell costimulatory molecule gene encodes B
7
-
1
. In another embodiment, the T cell costimulatory molecule gene encodes B
7
-
2
.
Another aspect of the invention provides proteins which bind CD
28
and/or CTLA
4
and contain a novel cytoplasmic domain. T cell costimulatory molecule genes which contain exons encoding different cytoplasmic domains which are used in an alternate manner have been discovered. Alternative splicing of mRNA transcripts of a T cell costimulatory molecule gene has been found to generate native T cell costimulatory molecules with different cytoplasmic domains. The existence of alternative cytoplasmic domain forms of T cell costimulatory molecules supports a functional role for the cytoplasmic domain in transmitting an intracellular signal within a cell which expresses the costimulatory molecule on its surface. This indicates that costimulatory molecules not only trigger an intracellular signal in T cells, but may also deliver a signal to the cell which expresses the costimulatory molecule. This is the first evidence that the interaction between a costimulatory molecule on one cell and its receptor on a T cell may involve bidirectional signal transduction between the cells (rather than only unidirectional signal transduction to the T cell).
In yet another aspect of the invention, proteins that bind CD
28
and/or CTLA
4
and contain a novel signal peptide domain are provided. T cell costimulatory molecule genes which contain exons encoding different signal peptide domains which are used in an alternate manner have been discovered. Alternative splicing of mRNA transcripts of the gene can generate native T cell costimulatory molecules with different signal peptide domains. The existence of alternative signal peptide domain forms of T cell costimulatory molecules also suggests a functional role for the signal peptide of T cell costimulatory molecules.
An isolated nucleic acid molecule of the invention can be incorporated into a recombinant expression vector and transfected into a host cell to express a novel structural form of a T cell costimulatory molecule. The isolated nucleic acids of the invention can further be used to create transgenic and homologous recombinant non-human animals. The novel T cell costimulatory molecules provided by the invention can be used to trigger a costimulatory signal in a T lymphocyte. These molecules can further be used
Borriello Francescopaolo
Freeman Gordon J.
Nadler Lee M.
Sharpe Arlene H.
Brigham & Woman's Hospital
Gambel Phillip
Lahive & Cockfield LLP
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