Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1998-01-15
2001-10-02
Kunz, Gary L. (Department: 1646)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C530S350000, C536S023500, C536S024300, C514S002600, C514S008100
Reexamination Certificate
active
06297028
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the polypeptide p43, to polypeptides which contain binding sites for at least two of NAD
+
, interleukin 2 receptor (IL-2R) &bgr;-chain, or IL-2R &ggr;-chain, to nucleic acid molecules containing the coding information for the aforementioned polypeptides, to antibodies specific for the aforementioned polypeptides, to antisense oligonucleotides, to pharmaceutical compositions containing the aforementioned polypeptides or nucleic acids, and to methods of producing the aforementioned polypeptides.
BACKGROUND OF THE INVENTION
Interleukin 2 (IL-2) plays a critical role in the regulation of proliferation and differentiation of hematopoietic cells (27, 29). IL-2 exerts its multiple biological activities through its binding to a specific cell surface receptor (IL-2R) (30), including protein tyrosine kinase (PTK) activation, and nuclear proto-oncogene expression which may be critical for cellular proliferation (16, 29). IL-2R contains at least three distinct subunits; the &agr;-chain, the &bgr;-chain and the &ggr;-chain (5, 9, 28). Among these subunits, both the IL-2R &bgr;- and &ggr;-chains belong to a newly identified superfamily of cytokine receptors, characterized by four conserved cysteines and the sequence Trp-Ser-X-Trp-Ser (the “WS motif SEQ ID NO: 18”) in their extracellular domains (1, 2). Notably, none of the IL-2R subunits possesses any known catalytic activity such as PTK activity.
The expression of different combinations of the IL-2R subunits gives rise to various forms of IL-2R, each of which exhibiting different binding affinity to IL-2 (28). The “high-affinity” IL-2R (Kd; 10
−11
) consists of the heterotrimer &agr;-, &bgr;- and &ggr;-chains, the “intermediate-affinity” IL-2R (Kd; 10
−9
) results from the heterodimer &bgr;- and &ggr;-chains, whereas the “low-affinity” IL-2R (Kd; 10
−8
) can be generated by expression of the &agr;-chain alone. IL-2R &bgr;-chain possesses the largest cytoplasmic domain, consisting of 288 amino acids (a.a.) and was shown to play a critical role in IL-2 signal transduction (8). When the human IL-2R &bgr;-chain cDNA was introduced into murine IL-3-dependent pro-B cell line BAF-B03, which normally expresses the endogenous IL-2R &agr;- and &ggr;-chains, but not the &bgr;-chain, these cells were capable of proliferating in response to IL-2 (3, 8). Further expression studies with deletion mutant cDNAs of the IL-2R &bgr;-chain revealed that a restricted cytoplasmic region of the IL-2R &bgr;-chain, designated the “serine-rich” region (S-region), is indispensable for c-myc gene induction and for mitogenesis following IL-2 stimulation of the BAF-B03 cells (26). Another cytoplasmic region of the IL-2R &bgr;-chain, rich in acidic amino acids, designated the “acidic” region (A-region), is required in addition to the S-region for the src-family PTK activation and p21
iras
activation and for c-foslc-jun gene induction following IL-2 stimulation of BAF-B03 cells (6, 7, 17, 24, 26). Several lines of evidence suggest that the IL-2R &ggr;-chain may also be critical for IL-2-induced signal transduction (29). Moreover, IL-2R &ggr;-chain is suggested to be a shared common component among the IL-2, IL-4 and IL-7 receptors and possibly other cytokine receptors (14, 15, 21, 23). Mutations of IL-2R &ggr;-chain have been found in X-linked severe combined immunodeficiency patients who show defects in T-cell development (22), providing evidence for the critical role of IL-2R &ggr;-chain in cytokine signaling. Furthermore, recent studies have indicated that the functional cooperation between the cytoplasmic domains of IL-2R &bgr;-chain and &ggr;-chain is critical for IL-2 signaling (11, 19, 20).
Because of the importance of IL-2R-mediated processes for normal body functions and disease, there is a need of better understanding of these processes as well as the need of new tools for influencing them.
SUMMARY OF THE INVENTION
The present invention provides a new IL-2R-associated protein, p43, and nucleic acid molecules containing the coding information for p43. Preferably, the p43 polypeptide has the amino acid sequence of SEQ ID NO: 2 (cf. FIGS.
1
A-
1
B):
Met Glu Phe Leu Lys Thr Cys Val Leu Arg Arg Asn Ala Cys Thr
Ala Val Cys Phe Trp Arg Ser Lys Val Val Gln Lys Pro Ser Val
Arg Arg Ile Ser Thr Thr Ser Pro Arg Ser Thr Val Met Pro Ala
Trp Val Ile Asp Lys Tyr Gly Lys Asn Glu Val Leu Arg Phe Thr
Gln Asn Met Met Met Pro Ile Ile His Tyr Pro Asn Glu Val Ile
Val Lys Val His Ala Ala Ser Val Asn Pro Ile Asp Val Asn Met
Arg Ser Gly Tyr Gly Ala Thr Ala Leu Asn Met Lys Arg Asp Pro
Leu His Val Lys Ile Lys Gly Glu Glu Phe Pro Leu Thr Leu Gly
Arg Asp Val Ser Gly Val Val Met Glu Cys Gly Leu Asp Val Lys
Tyr Phe Lys Pro Gly Asp Glu Val Trp Ala Ala Val Pro Pro Trp
Lys Gln Gly Thr Leu Ser Glu Phe Val Val Val Ser Gly Asn Glu
Val Ser His Lys Pro Lys Ser Leu Thr His Thr Gln Ala Ala Ser
Leu Pro Tyr Val Ala Leu Thr Ala Trp Ser Ala Ile Asn Lys Val
Gly Gly Leu Asn Asp Lys Asn Cys Thr Gly Lys Arg Val Leu Ile
Leu Gly Ala Ser Gly Gly Val Gly Thr Phe Ala Ile Gln Val Met
Lys Ala Trp Asp Ala His Val Thr Ala Val Cys Ser Gln Asp Ala
Ser Glu Leu Val Arg Lys Leu Gly Ala Asp Asp Val Ile Asp Tyr
Lys Ser Gly Ser Val Glu Glu Gln Leu Lys Ser Leu Lys Pro Phe
Asp Phe Ile Leu Asp Asn Val Gly Gly Ser Thr Glu Thr Trp Ala
Pro Asp Phe Leu Lys Lys Trp Ser Gly Ala Thr Tyr Val Thr Leu
Val Thr Pro Phe Leu Leu Asn Met Asp Arg Leu Gly Ile Ala Asp
Gly Met Leu Gln Thr Gly Val Thr Val Gly Ser Lys Ala Leu Lys
His Phe Trp Lys Gly Val His Tyr Arg Trp Ala Phe Phe Met Ala
Ser Gly Pro Cys Leu Asp Asp Ile Ala Glu Leu Val Asp Ala Gly
Lys Ile Arg Pro Val Ile Glu Gln Thr Phe Pro Phe Ser Lys Val
Pro Glu Ala Phe Leu Lys Val Glu Arg Gly His Ala Arg Gly Lys
Thr Val Ile Asn Val Val,
or SEQ ID NO: 4 (cf
FIG. 1C
, mouse p43):
Met Gly Val Leu Lys Thr Cys Val Leu Arg Arg Ser Ala Cys Ala
Ala Ala Cys Phe Trp Arg Arg Thr Val Ile Pro Lys Pro Pro Phe
Arg Gly Ile Ser Thr Thr Ser Ala Arg Ser Thr Val Met Pro Ala
Trp Val Ile Asp Lys Tyr Gly Lys Asn Glu Val Leu Arg Phe Thr
Gln Asn Met Met Leu Pro Ile Ile His Tyr Pro Asn Glu Val Ile
Ile Lys Val His Ala Ala Ser Val Asn Pro Ile Asp Val Asn Met
Arg Ser Gly Tyr Gly Ala Thr Ala Leu Asn Met Lys Arg Asp Pro
Leu His Met Lys Thr Lys Gly Glu Glu Phe Prd Leu Thr Leu Gly
Arg Asp Val Ser Gly Val Val Met Glu Cys Gly Leu Asp Val Lys
Tyr Phe Gln Pro Gly Asp Glu Val Trp Ala Ala Val Pro Pro Trp
Lys Gln Gly Thr Leu Ser Glu Phe Val Val Val Ser Gly Asn Glu
Val Ser His Lys Pro Lys Ser Leu Thr His Thr Gln Ala Ala Ser
Leu Pro Tyr Val Ala Leu Thr Ala Trp Ser Ala Ile Asn Lys Val
Gly Gly Leu Ser Asp Arg Asn Cys Lys Gly Lys Arg Ala Leu Ile
Leu Gly Ala Ser Gly Gly Val Gly Thr Phe Ala Ile Gln Val Met
Lys Ala Trp Gly Ala His Val Thr Ala Val Cys Ser Lys Asp Ala
Ser Glu Leu Val Arg Lys Leu Gly Ala Asp Glu Val Ile Asp Tyr
Thr Leu Gly Ser Val Glu Glu Gln Leu Lys Ser Leu Lys Leu Cys
Ala Phe Ile Leu Asp Asn Val Gly Gly Ser Thr Glu Thr Trp Ala
Leu Asn Phe Leu Lys Lys Trp Ser Gly Ala Thr Tyr Val Thr Leu
Val Thr Pro Phe Leu Leu Asn Met Asp Arg Leu Gly Val Ala Asp
Gly Met Leu Gln Thr Gly Val Thr Val Gly Thr Lys Ala Met Lys
His Leu Trp Gln Gly Val His Tyr Arg Trp Ala Phe Phe Met Ala
Ser Gly Pro Tyr Leu Asp Glu Ile Ala Glu Leu Val Asp Ala Gly
Lys Ile Arg Pro Val Ile Glu Arg Thr Phe Pro phe Ser Glu Val
Pro Glu Ala Phe Leu Lys Val Glu Arg Gly His Ala Arg Gly Lys
Thr Val Val Asn Val Val.
The invention is further related to polypeptides with p43-like activity or functional derivatives of p43, especially polypeptides which contain a binding site for at least NAD
+
and IL-2R &bgr;-chain, NAD
+
and IL-2R &ggr;-chain, or IL-2R &bgr;-chain and IL-2R &ggr;-chain. Functional derivatives may be variants, fragments, chemical derivatives, or fusion proteins of p43.
In a further aspect, the present invention is related to nucleic acid molecules containing the coding information for p43, polypeptides with p43-like activity, or functional derivatives. Preferably, a nucleic a
Barsoumian Edward Leon
Shibuya Hiroshi
Taniguchi Tadatsugu
Boehringer Ingelheim International GmbH
Brannock Michael
Kunz Gary L.
Sterne Kessler Goldstein & Fox P.L.L.C.
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