Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1997-06-06
2003-01-07
Kunz, Gary L. (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C930S010000
Reexamination Certificate
active
06504007
ABSTRACT:
INTRODUCTION
TECHNICAL FIELD
The present invention relates to novel uses of Glial-cell Derived Neurotrophic Factor (“GDNF”) and its receptor designated GDNFR&agr;, and provides GDNFR&agr;-encoding nucleic acid (SEQ ID NO:1) and amino acid sequences (SEQ ID NO:2). In particular, the invention relates to native sequence GDNFR&agr;, GDNFR&agr; variants, soluble GDNFR&agr; variants including GDNFR&agr; extracellular domain, chimeric GDNFR&agr;, and antibodies which bind to the GDNFR&agr; diagnostic techniques for identifying GDNF-related conditions, methods for identifying molecules homologous to GDNFR&agr;, and therapeutic techniques for the treatment of GDNF-related and GDNFR&agr;-related conditions, particularly kidney diseases.
BACKGROUND
Diseases of the nervous system are usually devastating and often lead to death. Neurological diseases are often chronic, which imposes a great social and economic burden. For example, stroke is the third leading cause of death in the United States, after heart disease and cancer. Neurotrophic factors, which are naturally-occurring proteins, such as insulin-like growth factors, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, -4/5 and- 6, ciliary neurotrophic factor, GDNF, and recently neurturin, have been proposed as potential means for enhancing specific neuronal cell survival to treat neurological diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, stroke, epilepsy, Huntington's disease, Parkinson's disease, and peripheral neuropathy. Neurotrophic factors, or neurotrophins, which influence growth and development of the vertebrate nervous system, are believed to play an important role in promoting the differentiation, survival, and function of diverse groups of neurons in the brain and periphery. Neurotrophic factors are believed to have important signaling functions in neural tissues, based in part upon the precedent established with nerve growth factor (NGF). NGF supports the survival of sympathetic, sensory, and basal forebrain neurons both in vitro and in vivo. Administration of exogenous NGF rescues neurons from cell death during development. Conversely, removal or sequestration of endogenous NGF by administration of anti-NGF antibodies promotes such cell death (Heumann,
J. Exp. Biol.,
132:133-150 (1987); Hefti,
J. Neurosci.,
6:2155-2162 (1986); Thoenen et al.,
Annu. Rev. Physiol,
60:284-335 (1980)).
Additional neurotrophic factors related to NGF have since been identified. These include brain-derived neurotrophic factor (BDNF) (Leibrock, et al.,
Nature,
341:149-152 (1989)), neurotrophin-3 (NT-3) (Kaisho, et al,
FEBS Lett.,
266:187 (1990); Maisonpierre, et al.,
Science,
247:1446 (1990); Rosenthal, et al.,
Neuron,
4:767 (1990)), and neurotrophin 4/5 (NT-4/5) (Berkmeier, et al.,
Neuron,
7:857-866 (1991)). GDNF, a distant member of the TGF-&bgr; super family, and neurturin (“NTN”) are two, recently identified, structurally related, potent survival factors for sympathetic sensory and central nervous system neurons (Lin et al.
Science
260:1130-1132 (1993); Henderson et al.
Science
266:1062-1064 (1994); Buj-Bello et al.,
Neuron
15:821-828 (1995); Kotzbauer et al.
Nature
384:467-470 (1996)). GDNF has been considered a potential therapeutic agent for Parkinson's disease, ALS, and Alzheimer's disease. The mechanism by which GDNF and NTN signals are transmitted has not been elucidated.
Neurotrophins, like NGF, affect their target cells through interactions with cell surface receptors. According to our current understanding, two kinds of transmembrane glycoproteins act as receptors for the known neurotrophins. Equilibrium binding studies have shown that neurotrophin-responsive neuronal cells possess a common low molecular weight (65,000-80,000 Daltons), a low affinity receptor typically referred to as p75
LNGFR
or p75, and a high molecular weight (130,000-150,000 Dalton) receptor. The high affinity receptors (trkA, trkB and trkC) are members of the trk family of receptor tyrosine kinases.
Receptor tyrosine kinases are known to serve as receptors for a variety of protein factors that promote cellular proliferation, differentiation, and survival. In addition to the trk receptors, examples of other receptor tyrosine kinases include the receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Typically, these receptors span the cell membrane, with one portion of the receptor being intracellular and in contact with the cytoplasm, and another portion of the receptor being extracellular. Binding of a ligand to the extracellular portion of the receptor induces tyrosine kinase activity in the intracellular portion of the receptor, with ensuing phosphorylation of various intracellular proteins involved in cellular signaling pathways.
Aberrant expression of receptor tyrosine kinases (“RTK”) correlates with transforming ability. For example, carcinomas of the liver, lung, breast and colon show elevated expression of Eph RTK. Unlike many other tyrosine kinases, this elevated expression can occur in the absence of gene amplification or rearrangement Moreover, Hek, a human RTK, has been identified as a leukemia-specific marker present on the surface of a pre-B cell leukemia cell line. As with Eph, Hek also was overexpressed in the absence of gene amplification or rearrangements in, for example, hemopoietic tumors and lymphoid tumor cell lines. Over-expression of Myk-1 (a murine homolog of human Htk (Bennett et al.,
J. Biol. Chem.,
269(19): 14211-8 (1994)) was found in the undifferentiated and invasive mammary tumors of transgenic mice expressing the Ha-ras oncogene. (Andres et al.,
Oncogene,
9(5):1461-7 (1994) and Andres et al.,
Oncogene,
9(8):2431 (1994)). Ret, the product of the c-ret proto-oncogene, is a member of the receptor tyrosine kinase superfamily.
In addition to their roles in carcinogenesis, a number of transmembrane tyrosine kinases have been reported to play key roles during development. Some receptor tyrosine kinases are developmentally regulated and predominantly expressed in embryonic tissues. Examples include Cek1, which belongs to the FGF subclass, and the Cek4 and Cek5 tyrosine kinases (Pasquale et al.,
Proc. Natl. Acad. Sci., USA,
86:5449-5453 (1989); Sajjadi et al.,
New Biol.,
3(8):769-78 (1991); and Pasquale,
Cell Regulation,
2:523-534 (1991). Eph family members are expressed in many different adult tissues, with several family members expressed in the nervous system or specifically in neurons (Maisonpierre et al.,
Oncogene,
8:3277-3288 (1993); Lai et al.,
Neuron,
6:691-704 (1991)).
The aberrant expression or uncontrolled regulation of any one of these receptor tyrosine kinases can result in different malignancies and pathological disorders. Therefore, there exists a need to identify means to regulate, control and manipulate receptor tyrosine kinases (“RTK”) and their associated ligands or GPI-linked receptors, in order to provide new and additional means for the diagnosis and therapy of receptor tyrosine kinase pathway-related disorders and cellular processes. The present application provides the clinician and researcher with such means by providing a novel neurotrophin-binding molecule that is also specific for interacting with a particular RTK receptor. New disease conditions are identified that are associated with this molecule and its neurotrophin ligand. These compounds and their methods of use, as provided herein, allow new and exquisite therapeutic control and specificity. Accordingly, it is an object of the present invention to provide an improved therapy for the prevention and/or treatment of neurological conditions and other conditions in which neurotrophic signaling pathways related to this novel receptor and its ligand play a role.
These and other objects of the invention will be apparent to the ordinarily skilled artisan upon consideration of the specification as a whole.
SUMMARY
The present invention is based, in part, on the present discovery that GDNF-defi
Klein Robert D.
Moore Mark W.
Rosenthal Arnon
Ryan Anne M.
Genentech Inc.
Hayes Robert C.
Knobbe Martens Olson & Bear LLP
Kunz Gary L.
LandOfFree
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