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  Antibodies to ocif-binding moleculesUSPTO Application #: 20070009520Title: Antibodies to ocif-binding molecules Abstract: A novel protein which binds to Osteoclastogenesis Inhibitory Factor (OCIF-binding molecule; OBM), a process for preparing the same, DNA encoding said protein, a protein having an amino acid sequence encoded by this DNA, a method for producing said protein by genetic engineering technique, and a pharmaceutical composition containing said protein. Screening methods for a substance for controlling expression of said protein using said protein and the DNA, a substance which inhibits or modulates the biological activity of said protein, or a receptor which transmits the action of said protein through binding to said protein, the substance obtained by the screening methods, and a pharmaceutical composition which contains this substance. An antibody for said protein, a process for preparing the same, a measuring method of said protein using the antibody, and a medicine comprising this antibody. (end of abstract)
Agent: Arnold & Porter LLP Attn:IPDocketing Dept. - Washington, DC, US Inventors: Kyoji Yamaguchi, Hisataka Yasuda, Nobuaki Nakagawa, Nobuyuki Shima, Masahiko Kinosaki, Eisuke Tsuda, Masaaki Goto, Kazuki Yano, Akihiro Tomoyasu, Fumie Kobayashi, Naohiro Washida, Ken Takahashi, Tomonori Morinaga, Kanji Higashio USPTO Applicaton #: 20070009520 - Class: 424144100 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Immunoglobulin, Antiserum, Antibody, Or Antibody Fragment, Except Conjugate Or Complex Of The Same With Nonimmunoglobulin Material, Monoclonal Antibody Or Fragment Thereof (i.e., Produced By Any Cloning Technology), Binds Receptor, Receptor Integral To Or Derived From A Lymphocytic Or Lymphocytic-like Cell (e.g., Nk Cell, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070009520. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10/854,300 filed May 27, 2004, which is a continuation of U.S. application Ser. No. 10/167,182, filed Jun. 11, 2002, which is a divisional of U.S. application Ser. No. 09/202,455, filed Dec. 15, 1998 (now abandoned), which is a national phase application under 35 U.S.C. .sctn. 371 of International Application No. PCT/JP98/01728, filed Apr. 15, 1998, which claims priority to Japanese Patent Application No. 097808/1997, filed Apr. 15, 1997, Japanese Patent Application No. 151434/1997, filed Jun. 9, 1997, Japanese Patent Application No. 217897/1997, filed Aug. 12, 1997, Japanese Patent Application No. 224803/1997, filed Aug. 21, 1997 and Japanese Patent Application No. 332241/1997, filed Dec. 2, 1997. FIELD OF TECHNOLOGY [0002] The present invention relates to a novel protein (OCIF-binding molecule, the protein may be hereinafter called OBM) which binds to osteoclastogenesis inhibitory factor (hereinafter it may be called OCIF) and a method to produce this protein. [0003] The present invention also relates to DNA encoding this protein, proteins containing the amino acid sequence encoded by this DNA, a method for the preparation of this protein utilizing genetic engineering techniques, and pharmaceutical compositions comprising this protein. [0004] The present invention further relates to methods for screening, using this protein and the DNA, substances to control the expression of this protein, substances inhibiting or regulating the biological activity of this protein, or receptors transducing the signal of the protein by interacting with this protein, to substances obtained by the screening, and to pharmaceutical compositions which comprise the resulting substances. [0005] The present invention further relates to antibodies against this protein, methods for preparing the antibodies, and pharmaceutical compositions comprising these antibodies. BACKGROUND OF THE INVENTION [0006] Bone metabolism is dependent on the overall activity of osteoblasts which control bone formation and osteoclasts which control bone resorption. Abnormality of bone metabolism is considered to be caused by an imbalance of the bone formation and the bone resorption. Osteoporosis, hypercalcemia, Paget's disease, renal osteodystrophy, chronic rheumarthritis, osteoarthristis, and the like are known as diseases accompanying abnormality of bone metabolism. Osteoporosis is a typical disease caused by such abnormality of bone metabolism. This disease is generated when bone resorption by osteoclasts exceeds bone formation by osteoblasts. The disease is characterized by a decrease in both the bone calcified material and the bone matrix. Although the mechanism of this disease is not completely elucidated, the disease causes aches in bones, makes them fragile, and may result in fracturing. This disease is becoming a social problem because it increases the number of bedridden aged persons as the aged population becomes larger. Development of therapeutic agent for this disease is urgently desired. Disease due to a decrease in bone mass is expected to be cured by suppressing bone resorption, accelerating bone formation, or improving the balance between bone resorption and formation. Bone formation is expected to increase by accelerating proliferation, differentiation, or activation of osteoblasts which form bone, or by suppressing proliferation, differentiation, or activation of osteoclasts which resorb bone. In recent years, strong interest has been directed to hormones, low molecular weight substances, or physiologically active proteins exhibiting such activities, and energetic basic research and development is underway on these subjects. [0007] Drugs such as a calcitonin agents, active-form vitamin D.sub.3 agents, hormone agents containing estradiol, ipriflavon, vitamin K.sub.2, and bisphosphonate compounds have already been known as drugs to treat and shorten the treatment period of diseases related to bone. Clinical tests are in progress on active-form vitamin D.sub.3 derivatives, estradiol derivatives, and bisphosphonate compounds of the second and the third generation to develop therapeutic agents with excellent efficacy and minimal side effects. [0008] However, therapies using these agents were found not necessarily satisfactory in terms of efficacy and therapeutic results. Development of novel therapeutic agents which are safer and with higher efficacy is urgently desired. Some agents used for the treatment of diseases related to bone metabolism are used only limitedly due to their side effects. Furthermore, treatments using two or more agents in combination are currently the mainstream in the treatment of diseases related to bone metabolism such as osteoporosis. From such a point of view, development of drugs having action mechanisms different from those of conventional drugs, and exhibiting a higher efficacy and minimal side effects is desired. [0009] As mentioned above, the cells controlling bone metabolism are osteoblasts and osteoclasts. These cells are known to have close mutual interactions called "coupling". Specifically, cytokines such as Interleukins 1 (IL-1), 3 (IL-3), 6 (IL-6), and 11 (IL-11), granulocytic macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), Interferon-.gamma. (IFN-.gamma.), tumor necrosis factor .alpha. (TNF-.alpha.), and transforming growth factor-.beta. (TGF-.beta.), secreted by osteoblastic stromal cells are known to accelerate or suppress differentiation or maturation of osteoclasts (Raisz: Disorders of Bone and Mineral Metabolism, 287-311, 1992; Suda et al.: Principles of Bone Biology, 87-102, 1996; Suda et al.: Endocrine Reviews, 4, 266-270, 1995, Lacey et al.: Endocrinology, 186, 2369-2376, 1995). It has been reported that osteoblastic stromal cells play an important role in the differentiation and maturation of osteoclasts, as well as in osteoclast functions such as bone resorption by mature osteoclasts, through cell-to-cell contact with immature osteoclast precursors or mature osteoclasts. [0010] A factor called osteoclast differentiation factor (ODF, Suda et al.: Endocrine Rev. 13:66-80, 1992; Suda et al.: Bone 17, 87S-91S, 1995) is thought to be expressed on the membrane of osteoblastic stromal cells and involved in the formation of osteoclasts through cell-to-cell contact. According to this hypothesis, an ODF receptor is present in the precursor cells of osteoclasts. However, so far neither the ODF nor the receptor has been purified or identified. There are also no reports relating to their characteristics, action mechanism, or structure. Thus, the mechanism involved in differentiation and maturation of osteoclasts has not yet been sufficiently elucidated. Clarification of this mechanism will greatly contribute not only to the basic medicine, but also to the development of novel drugs for the treatment of diseases associated with abnormality of bone metabolism. [0011] The present inventors have conducted extensive studies in view of this situation and discovered an osteoclastogenesis inhibitory factor (OCIF) in a culture broth of human embryonic lung fibroblast, IMR-90 (ATCC Deposition No. CCL186) (WO 96/26217). [0012] The present inventors have been successful in cloning DNA encoding OCIF, production of recombinant OCIF in animal cells, and confirmation of in vivo pharmaceutical effects (improving effect on bone metabolism, etc.) of the recombinant OCIF. OCIF is expected to be used as an agent for the prevention or treatment of diseases related to abnormality of bone metabolism, with higher efficacy than conventional drugs and less side effects. DISCLOSURE OF THE INVENTION [0013] The present inventors have searched for a protein which binds to osteoclastogenesis inhibitory factor (OCIF) and discovered that an OCIF-binding protein is specifically expressed on the osteoblastic stromal cells cultured in the presence of a bone resorption factor such as active-form vitamin D.sub.3 and parathyroid hormone (PTH). In addition, the present inventors have investigated the characteristics and physiological functions of this OCIF-binding protein and found that the protein exhibits biological activity of a factor which supports or promotes the osteoclast differentiation and maturation from immature precursors of osteoclasts. These findings have led to the completion of the present invention. Further investigation into the protein of the present invention has proven that this is an important protein controlling the differentiation and maturation of osteoclasts from immature precursors of osteoclasts in a co-culture system of the osteoblastic stromal cells and spleen cells. The success in identification and isolation of the protein which functions as a factor supporting or promoting differentiation and maturation of osteoclasts in the present invention has enabled screening for a novel medicine useful for abnormality of bone metabolism based on mechanism of bone metabolism utilizing the protein of the present invention. [0014] Accordingly, an object of the present invention is to provide a novel protein (OCIF-binding molecule or OBM) which binds to osteoclastogenesis inhibitory factor (OCIF), and a method to produce this protein. [0015] Another object of the present invention is to provide DNA encoding this protein, proteins containing an amino acid sequence encoded by this DNA, a method for producing this protein utilizing genetic engineering techniques, and pharmaceutical compositions comprising this protein. [0016] A further object of the present invention is to provide methods for screening substances which control expression of this protein using this protein and the DNA, substances inhibiting or regulating the biological activity of this protein, receptors transducing the action of the protein by binding to the protein, substances obtained by the screening, and pharmaceutical compositions which comprises these substances. [0017] A still further object of the present invention is to provide antibodies against this protein, methods for preparing the antibodies, and pharmaceutical compositions comprising these antibodies. [0018] The protein of the present invention has the following physicochemical properties and biological activity. [0019] (a) Affinity: specifically binds to the osteoclastogenesis inhibitory factor (OCIF) and exhibits high affinity to OCIF (dissociation constant on cell membrane: Kd=10.sup.-9 M or less); [0020] (b) Molecular weight: has a molecular weight of approximately 30,000-40,000 when determined by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) under non-reducing conditions and an apparent molecular weight of approximately 90,000-110,000 when cross-linked to a monomer form OCIF; and [0021] (c) Biological activity: exhibits activity supporting or promoting osteoclast differentiation and maturation in a co-culture system of the mouse osteoblastic stromal cells and mouse spleen cells in the presence of bone resorption factors such as active-form vitamin D.sub.3 and parathyroid hormone (PTH). [0022] A co-culture system of ST2, a mouse osteoblastic stromal cell line, and mouse spleen cells in the presence of active-form vitamin D.sub.3 or PTH is well known as a typical in vitro culture system for osteoclast formation. The cells expressing the protein of the present invention can be determined by testing the binding of OCIF to mouse osteoblastic stromal cells or mouse spleen cells cultured in the presence or absence of active-form vitamin D.sub.3. The protein of the present invention is specified as the protein which is induced specifically on the osteoblastic stromal cells cultured in the presence of an osteotropic factor such as active-form vitamin D.sub.3 or PTH. In addition, the protein of the invention can be specified as a protein exhibiting biological activity supporting or promoting differentiation and maturation of osteoclasts from the following results. That is, the osteoclast formation is inhibited dose dependently by the addition of 1 to 40 ng/ml of OCIF to the above-mentioned co-culture system in the presence of the active-form vitamin D.sub.3, the time course of expression of the protein of the present invention on ST2 cells in the presence of active-form vitamin D.sub.3 well correlates with the time course of osteoclast formation in the co-culture. In addition, the amount of protein of the present invention expressed on ST2 cells correlates with the capability of the cells to support the osteoclast formation, and the binding of OCIF to the protein of the present invention on the ST2 cells completely suppresses osteoclasts formation. [0023] The affinity of the protein of the present invention to OCIF can be evaluated by labeling OCIF and examining the binding of the labeled OCIF to the surface of animal cell membrane. OCIF can be labeled by a conventional protein-labeling method such as radioisotope or fluorescent labeling. Labeling of tyrosine residues with .sup.125I can be given as a specific example of labeling of the OCIF with an radioisotope. Labeling methods such as iodogen method, chloramine T method, and enzymatic method can be utilized. The binding of the labeled OCIF to the surface membrane of animal cell can be tested by a conventional method. The addition of unlabeled OCIF to the medium used for the binding assay to a concentration, 100 to 400 times the concentration of labeled OCIF, ensures measurement of non-specific binding. The amount of specific binding of OCIF can be calculated by subtracting the amount of non-specific binding from the total amount of binding of the labeled OCIF. The affinity of the protein of the present invention expressed on the cell membrane to OCIF can be evaluated by changing the amount of labeled OCIF and analyzing the specific binding by Scatchard plot. Continue reading... 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