Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
1998-02-06
2002-02-12
Davenport, Avis M. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C530S300000, C514S009100, C514S011400
Reexamination Certificate
active
06346602
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to molecules which have structures and functions that mimic the gamma chain that is shared by several cytokine receptors. The present invention relates to the use of such molecules to modulate cytokine activity and cytokine mediated functions.
BACKGROUND OF THE INVENTION
A family of related cytokine receptors including the receptors for IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 have been reported to share a common protein chain, the &ggr;-chain, for maximal ligand induced receptor binding and signaling. The &ggr;-chain is a member of the cytokine receptor superfamily which includes receptors for growth hormone, erythropoietin, IL-3, IL-2, IL-4, IL-7, IL-6 and GM-CSF. The &ggr;-chain is a 64 kd protein with a fibronectin type II and CKR-SF domain which share structural homology.
The crystal structure of the human growth hormone receptor has been published by deVos A. M., et al. 1992
Science
255:306-312, which is incorporated herein by reference, and shows that the receptors form a homodimer to bind ligand and induce a signal. The receptors for IL-4 have been shown to be in the form of a heterodimer consisting of IL-4&agr; and the common &ggr;-chain. A model for the human IL-4:IL-4-Receptor interaction has been published by Gustchina, A. et al. 1995 PROTEINS:
Structure, Function and Genetics
21:140-148, which is incorporated herein by reference.
Cytokine:receptor complexes are very important mediators of many immune responses. For example, T cell growth and differentiation is regulated in part by IL-2, IL-4, IL-7, IL-9, and IL-15. These cytokines have also been reported to play a role in other immunological functions as well.
Without the &ggr;-chain, the cytokine receptors which normally form complexes with the &ggr;-chain are much less efficient in binding their ligands and thus transmitting their signals to the target cells. Evidence for the central role of the &ggr;-chain includes the findings that mutations in this receptor have been demonstrated to be the causative factor in the development of severe combined immunodeficiency. Recently, Boussiotis, V. A. et al. 1994
Science
266:1039-1047, which is incorporated herein by reference, demonstrated that the development of T cell anergy can be abrogated by signaling through this receptor by various means.
The function and activity of cells of the immune system are regulated and directed by cytokine:receptor interactions as is signaling which induces growth and proliferation. The activation of T cells and B cells is regulated by cytokine:receptor interactions including cytokine:receptor interactions involving receptors which include the &ggr;-chain in a heterodimer.
There is a need for pharmaceutical compositions which can effectively inhibit the immune responses mediated by cytokine:receptor interactions. There is a need for a method of inhibiting cytokine mediated cell activation, function, growth and/or proliferation. There is a need for pharmaceutical compositions which can effectively inhibit signaling that involves receptors which include the &ggr;-chain. There is a need for compositions and methods which can inhibit or suppress immune responses in order to therapeutically or prophylactically treat individuals who have conditions, diseases or disorders involving immune abnormal or undesirable immunological activity.
SUMMARY OF THE INVENTION
The present invention relates to peptide mimics of the loops on the &ggr;-chain which either interact with cytokines or the partners of the &ggr;-chain in heterodimeric cytokine receptors that include the &ggr;-chain. The peptides of the present invention are based on human and murine &ggr;-chain sequences. The sequences homology for the human and murine &ggr;-chain is high (71% identical and 82% similar) making the translation from one species to the next more direct.
The peptide mimics bind to the cytokine or partner receptor and inhibit cytokine activity. Inhibitors of the common &ggr;-chain inhibit the function of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 by preventing their binding to their respective receptors. Thus, the inhibition of these cytokine mediated events leads to immuno-suppressive responses which are beneficial for the prevention or treatment of numerous auto-immune diseases and graft rejection following various types of transplant procedures as well as diseases associated with hyperproliferation of T cells and/or B cells. For example, many lymphomas are dependent on some of these cytokines (IL-2 for T cell lymphomas and IL-4 for B cell lymphomas) for growth.
The present invention relates to peptides that consist of 5 to 25 amino acids including: SEQ ID NO:1 IQLYQTF, SEQ ID NO:2 IHLYQTF, SEQ ID NO:3 CLQYLV, SEQ ID NO:4 CLEHLV, SEQ ID NO:5 CLQYLT, SEQ ID NO:6 CLEHLT, SEQ ID NO:7 CLQYLTQ, SEQ ID NO:8 CLEHLTQ, SEQ ID NO:9 PIAGSSQQ, SEQ ID NO:36 PICGSSQQ, SEQ ID NO:10 PLCGSAQH, SEQ ID NO:11 PLAGSAQH, SEQ ID NO:12 NHEPRFLS, SEQ ID NO:13 DYRHKFSL, SEQ ID NO:14 LNLQNL, SEQ ID NO:15 LKLQNL, SEQ ID NO:16 NLSESQL, SEQ ID NO:17 KLSEQL or such an amino acid sequence with one or more conservative substitutions, wherein the peptide inhibits cytokine mediated signal transduction.
The peptides of the invention preferably have constrained conformations and most preferably are cyclic. In preferred embodiments, cysteine residues are provided at the termini of the peptides to form di-sulfide bonds which result in the formation of cyclic peptides.
According to some embodiments of the present invention, peptides are selected from the group consisting of: SEQ ID NO:18 CIQLYQTFC, SEQ ID NO:19 CIHLYQTFC, SEQ ID NO:20 CLQYLVC, SEQ ID NO:21 CLEHLVC, SEQ ID NO:22 CLQYLTC, SEQ ID NO:23 CLEHLTC, SEQ ID NO:24 CLQYLTQC, SEQ ID NO:25 CLEHLTQC, SEQ ID NO:26 CPIAGSSQQC, SEQ ID NO:37 CPICGSSQQC, SEQ ID NO:27 CPLCGSAQHC, SEQ ID NO:28 CPLAGSAQHC, SEQ ID NO:29 CNHEPRFLSC, SEQ ID NO:30 CDYRHKFSLC, SEQ ID NO:31 CLNLQNLC, SEQ ID NO:32 CLKLQNLC, SEQ ID NO:33 CNLSESQLC, SEQ ID NO:34 CKLSESQLC and derivative peptides thereof. The derivative peptides consist of amino acid sequences which contain one or more conservative substitutions. Conservative substitutions include the following:
I may be substituted with V, A or L;
Q may be substituted with N;
L may be substituted with V, A or I;
Y may be substituted with F;
V may be substituted with I, A or L;
S may be substituted with T;
A may be substituted with V, I or L;
N may be substituted with Q;
E may be substituted with D;
F may be substituted with Y;
D may be substituted with E; and
I may be substituted with V, A or L.
In some preferred embodiments, the V in sequences SEQ ID NO:3 CLQYLV and SEQ ID NO:4 CLEHLV are substituted with T to improve solubility in aqueous solutions. Accordingly, peptides SEQ ID NO:22 CLQYLTC, SEQ ID NO:23 CLEHLTC, SEQ ID NO:24 CLQYLTQC and SEQ ID NO:25 CLEHLTQC are provided.
The peptides of the invention are derived from sequences of the murine or human cytokine receptor common gamma chain.
The peptides correspond to murine cytokine receptor gamma common chain residues SEQ ID NO:l IQLYQTF (100-106), SEQ ID NO:3 CLQYLV (161-166), PICGSSQQ (207-214), SEQ ID NO:12 NHEPRFLS (181-188), SEQ ID NO:14 LNLQNL (124-129), SEQ ID NO:16 NLSESQL (142-148) and the corresponding sequences from the human cytokine receptor gamma common chain, i.e. SEQ ID NO: 2 IHLYQTF, SEQ ID NO:4 CLEHLV, SEQ ID NO:
11
PLAGSAQH, SEQ ID NO:13 DYRHKFSL, SEQ ID NO:15 LKLQNL and SEQ ID NO:17 KLSEQL.
The peptides SEQ ID NO:18 CIQLYQTFC, SEQ ID NO:19 CIHLYQTFC, SEQ ID NO:20 CLQYLVC, SEQ ID NO:21 CLEHLVC, SEQ ID NO:26 CPIAGSSQQC, SEQ ID NO:37 CPICGSSQQC, SEQ ID NO:27 CPLCGSAQHC, SEQ ID NO:28 CPLAGSAQHC, SEQ ID NO:29 CNHEPRFLSC, SEQ ID NO:30 CDYRHKFSLC, SEQ ID NO:31 CLNLQNLC and SEQ ID NO:32 CLKLQNLC are modeled to mimic the regions of the cytokine receptor gamma common chain predicted to interact with ligands and the peptides SEQ ID NO:33 CNLSESQLC and SEQ ID NO:34 CKLSESQLC are modeled to mimic the regions of the cytokine receptor gamma common chain predicted to interact with other cytokine receptor chains with which the gamm
Korngold Robert
Townsend Robert Martin
Davenport Avis M.
Thomas Jefferson University
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
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