Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-14
2004-08-10
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S185100, C424S192100
Reexamination Certificate
active
06774106
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to proteins that are involved in inflammation and immunomodulation, survival, or activation or in lymphoproliferative disorders or other cancers. The invention further relates to proteins related to the tumor necrosis factor (TNF)
erve growth factor (NGF) superfamily and related nucleic acids, expression vectors, host cells, and binding assays. The specification also describes compositions and methods for the treatment of immune-related and inflammatory, autoimmune and other immune-related diseases or disorders, such as rheumatoid arthritis (RA), Crohn's disease (CD), lupus, and graft versus host disease (GvHD) as well as for treatment of lymphoproliferative diseases and other cancers.
BACKGROUND OF THE INVENTION
After years of study in necrosis of tumors, tumor necrosis factors (TNFs) &agr; and &bgr; were finally cloned in 1984. The ensuing years witnessed the emergence of a superfamily of TNF cytokines, including fas ligand (FasL), CD27 ligand (CD27L), CD30 ligand (CD30L), CD40 ligand (CD40L), TNF-related apoptosis-inducing ligand (TRAIL, also designated AGP-1), osteoprotegerin binding protein (OPG-BP or OPG ligand), 4-1BB ligand, LIGHT, APRIL, and TALL-1. Smith et al. (1994),
Cell,
76: 959-962; Lacey et al. (1998),
Cell,
93: 165-176; Chichepotiche et al. (1997),
J. Biol. Chem.,
272: 32401-32410; Mauri et al. (1998),
Immunity,
8: 21-30; Hahne et al. (1998),
J. Exp. Med.,
188: 1185-90; Shu et al. (1999),
J. Leukocyte Biology,
65: 680-3. This family is unified by its structure, particularly at the C-terminus. In addition, most members known to date are expressed in immune compartments, although some members are also expressed in other tissues or organs, as well. Smith et al. (1994),
Cell
76: 959-62. All ligand members, with the exception of LT-&agr;, are type II transmembrane proteins, characterized by a conserved 150 amino acid region within C-terminal extracellular domain. Though restricted to only 20-25% identity, the conserved 150 amino acid domain folds into a characteristic &bgr;-pleated sheet sandwich and trimerizes. This conserved region can be proteolyticaly released, thus generating a soluble functional form. Banner et al. (1993),
Cell,
73: 431-445.
Many members within this ligand family are expressed in lymphoid enriched tissues and play important roles in the immune system development and modulation. Smith et al. (1994). For example, TNF&agr; is mainly synthesized by macrophages and is an important mediator for inflammatory responses and immune defenses. Tracey & Cerami (1994),
Annu. Rev. Med.,
45: 491-503. Fas-L, predominantly expressed in activated T cell, modulates TCR-mediated apoptosis of thymocyts. Nagata, S. & Suda, T. (1995)
Immunology Today,
16:39-43; Castrim et al. (1996),
Immunity,
5:617-27. CD40L, also expressed by activated T cells, provides an essential signal for B cell survival, proliferation and immunoglobulin isotype switching. Noelle (1996),
Immunity,
4:415-9.
The cognate receptors for most of the TNF ligand family members have been identified. These receptors share characteristic multiple cysteine-rich repeats within their extracellular domains, and do not possess catalytic motifs within cytoplasmic regions. Smith et al. (1994). The receptors signal through direct interactions with death domain proteins (e.g. TRADD, FADD, and RIP) or with the TRAF proteins (e.g. TRAF2, TRAF3, TRAF5, and TRAF6), triggering divergent and overlapping signaling pathways, e.g. apoptosis, NF-&kgr;B activation, or JNK activation. Wallach et al. (1999),
Annual Review of Immunology
17: 331-67. These signaling events lead to cell death, proliferation, activation or differentiation. The expression profile of each receptor member varies. For example, TNFR1 is expressed on a broad spectrum of tissues and cells, whereas the cell surface receptor of OPGL is mainly restricted to the osteoclasts. Hsu et al. (1999)
Proc. Natl. Acad. Sci. USA,
96:3540-5. Such proteins are believed to play a role in inflammatory and immune processes, suggesting their usefulness in treating autoimmune and inflammatory disorders.
A number of research groups have recently identified TNF family ligands with the same or substantially similar sequence, but they have not identified the associated receptor. The ligand has been variously named neutrokine-&agr; (WO 98/18921, published May 7, 1998), 63954 (WO 98/27114, published Jun. 25, 1998), TL5 (EP 869 180, published Oct. 7, 1998), NTN-2 (WO 98/55620 and WO 98/55621, published Dec. 10, 1998), TNRL1-alpha (WO 9911791, published Mar. 11, 1999), kay ligand (WO99/12964, published Mar. 18, 1999), and AGP-3 (U.S. Prov. App. No. 60/119,906, filed Feb. 12, 1999 and No. 60/166,271, filed Nov. 18, 1999, respectively). Each of these references is hereby incorporated by reference. Hereinafter, this protein sequence is referred to as “AGP-3.”
A recent paper has identified two previously known proteins as receptors for AGP-3. Gross et al. (2000),
Nature
404: 995-9. The first receptor was previously identified as a lymphocyte surface receptor named Transmembrane Activator and CAML Interactor (TACI). See WO 98/39361, published Sep. 11, 1998, and von Bulow & Bram (1997),
Science,
278:138-140, each of which is hereby incorporated by reference in its entirety. According to these references, TACI binds an intracellular cyclophilin ligand designated CAML, which modulates the calcium signaling pathway in lymphocytes.
The second receptor identified for AGP-3 is the so-called B cell maturation protein (BCMA). The human BCMA gene was discovered by molecular analysis of a t(4;16) translocation, which characteristic of a human T cell lymphoma. Laabi et al. (1993),
EMBO J.
11: 3897-3904. BCMA mRNA was reported to be found mainly in lymphoid tissues. Human BCMA cDNA encodes a 184 amino acids protein (185 residues for the mouse), and the literature reports no obvious similarity with any known protein or motif, and its function remained unknown. The protein was reported to reside in the Golgi apparatus (Gras et al. (1995),
Intl. Immunol.
7: 1093-1106). Recent speculation suggested that BCMA may be a distant member of the TNFR super family. Madry et al. (1998),
Intl. Immunol.
10: 1693-1702.
A ligand called APRIL or G70 is a TNF family ligand that remains without a receptor reported in the literature. According to the literature, APRIL is associated with prostate cancer, breast cancer, Alzheimer's disease, immune disorders, inflammatory disorders, and gestational abnormalities. See WO 99/00518 (Jun. 26, 1997); WO 99/11791 (Sep. 5, 1997); WO 99/12965 (Sep. 12, 1997); EP 911 633 (Oct. 8, 1997); EP 919 620 (Nov. 26, 1997); WO 99/28462 (Dec. 3, 1997); WO 99/33980 (Dec. 30, 1997); WO 99/35170 (Jan. 5, 1998); and Hahne et al. (1998),
J. Exp. Med.
188: 1185-90. (Each of the foregoing references is hereby incorporated by reference in its entirety.) A recent paper described APRIL isoforms and suggested that APRIL causes cell death. Kelly et al. (2000),
Cancer Res.
60: 1021-7. The art would benefit from identification of a receptor for APRIL and a clarification of its activity.
SUMMARY OF THE INVENTION
It has now been found that sG70 (APRIL) binds to cell-surface receptors on T and B lymphoma cells resulting in stimulation of proliferation of primary human and mouse B and T cells both in vitro and in vivo. It has now been found that BCMA and TACI are cell-surface receptors for APRIL. It has also been found that APRIL competes with AGP3′s binding to TACI and BCMA. Furthermore it is shown here that sBCMA inhibits APRIL and AGP3 binding to its receptors. sBCMA ameliorates T cell dependent and T cell independent humoral immune responses in vivo. In addition it has now been found that sTACI inhibits APRIL and AGP3 binding to its receptors and ameliorates T cell dependent and T cell independent humoral immune responses in vivo. In addition it has now been found that sBCMA reduces lymphoma and colon carcinoma cell tumor growth in vivo. It has also now been found that sBCMA increases survival a
Theill Lars Eyde
Yu Gang
Amgen Inc.
Chan Christina
Haddad Maher
Mohr Randolph N.
LandOfFree
Methods and compositions of matter concerning APRIL/G70,... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods and compositions of matter concerning APRIL/G70,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and compositions of matter concerning APRIL/G70,... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3293870