English:
[0002] The present invention relates to FGF21 -associated disorders including cancers and vascular diseases. More particularly, the invention relates to methods for treating cancer and vascular diseases, compositions for treating cancer and vascular diseases, and methods and compositions for diagnosing and/or detecting cancer and vascular diseases.
[0004] Fibroblast growth factor 21 (FGF21 ) is a member of the FGF protein family (US Patent No. 6,716,626). The FGF proteins identified to date belong to a family of signaling molecules that regulate growth and differentiation of a variety of cell types. The significance of FGF proteins to human physiology and pathology relates in part to their roles in embryogenesis, in blood vessel development and growth, and in bone growth. The majority of FGF family members have been associated with cellular activities including mitosis, development, transformation, angiogenesis, and cell survival. Several members of the FGF family and their biological roles are described in Crossley et al, Development 121:439-451 (1995); Ohuchi et al, Development 124:2235-2244 (1997); Gemel et al, Genomics 35:253-257 (1996); and Ghosh et al, Cell Growth and Differentiation 7:1425-1434 (1996).
[0007] Vascular diseases affect the circulatory system and include diseases such as coronary artery disease (CAD) and peripheral artery disease (PAD). CAD is the major cause of death in the United States, and studies have linked defects in angiogenesis to the progression of CAD (e.g., Matsunaga, et al, Am J Physiol Heart Circ Physiol 288: H2042-H2046, 2005). Studies in animal models of ischemia show that administration of angiogenic growth factors can augment nutrient perfusion through neovascularization. Clinical trials of therapeutic angiogenesis using growth factors such as VEGF and FGF in patients with end-stage CAD have shown increases in exercise time and reductions in anginal symptoms. Angiogenesis has also been shown to improve blood flow following cardiac infarction (Takeshita et al., J. Clin. Invest. 93:662-670, 1994). Thus angiogenic factors are promising therapeutics for the treatment of vascular disease.
[0008] To date, however, the role of FGF21 in cancer and vascular disease has not been fully elucidated. Accordingly there is a need to identify compositions and methods that modulate FGF21. The present invention is directed to these, as well as other, important needs.
[000129] Homology may also be at the polypeptide level. In some embodiments, polypeptides are about 85%, about 90%, about 92%, about 94%, about 95%, about 97%, about 98%, about 99% and about 100% homologous to SEQ ID NO:2, or a portion thereof. In some embodiments the polypeptides have up to 5, up to 10, up to 15, up to 20 or up to 30 amino acid insertions, deletions or substitutions.
[000149] The present invention also provides methods and compositions for the treatment, inhibition, and management of a vascular disorder or disease that has become partially or completely refractory to current or standard treatments.
[000159] In some embodiments the antibody is a humanized antibody. Humanized antibodies may be achieved by a variety of methods including, for example: (1) grafting the non-human complementarity determining regions (CDRs) onto a human framework and constant region (a process referred to in the art as "humanizing"), or, alternatively, (2) transplanting the entire non- human variable domains, but "cloaking" them with a human-like surface by replacement of surface residues (a process referred to in the art as "veneering"). In the present invention, humanized antibodies will include both "humanized" and "veneered" antibodies. Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al., Bio/Technology 10, 779-783 (1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar, Intern. Rev. Immunol. 13 65-93 (1995); Jones et al., Nature 321:522-525 (1986); Morrison et al., Proc. Natl. Acad. Sci, U.S.A., 81 :6851-6855 (1984); Morrison and Oi, Adv. Immunol., 44:65-92 (1988); Verhoeyer et al., Science 239:1534-1536 (1988); Padlan, Molec. Immun. 28:489-498 (1991); Padlan, Molec. Immunol. 31(3): 169-217 (1994); and Kettleborough, CA. et al., Protein Eng. 4(7):773-83 (1991) each of which is incorporated herein by reference. [000160] Antibodies of the present invention may function through different mechanisms. In some embodiments, antibodies trigger antibody-dependent cellular cytotoxicity (ADCC), a lytic attack on antibody-targeted cells. In some embodiments, antibodies have multiple therapeutic functions, including, for example, antigen-binding, induction of apoptosis, and complement-dependent cellular cytotoxicity (CDC).
[000239] The present invention further provides methods of modulating an FGF21 -related biological activity in a patient. The methods comprise administering to the patient an amount of an FGF21 modulator effective to modulate one or more FGF21 biological activities. Suitable assays for measuring FGF21 biological activities are set forth supra and infra.

中文:
[0002]本发明涉及FGF21-相关病症,包括癌症和血管疾病。更特别的,发明涉及治疗癌症和血管疾病的方法,治疗癌症和血管疾病的组合物,以及用于诊断和/或检测癌症和血管疾病的方法和组合物。
[0004]成纤维细胞生长因子21(FGF21)是FGF蛋白质家族的成员(美国专利号6,716,626)。目前鉴定FGF蛋白属于信号分子家族,调节多种细胞类型的生长和分化。FGF蛋白对人生理学和病理学的重要性,部分的涉及它们在胚胎发生、血管发育和生长,以及骨骼生长中的作用。FGF家族的大多数成员与细胞活动相关,包括有丝分裂、发育、转化、血管发生和细胞存活。FGF家族的一些成员及其生物学作用描述在Crossley等人,Development 121:439-451(1995);Ohuchi等人,Development 124:2235-2244(1997);Gemel等人,Genomics 35:253-257(1996);和Ghosh等人,CellGrowth and Differentiation 7:1425-1434(1996)。
[0007]血管疾病影响循环系统,包括疾病例如冠状动脉病(CAD)和外周动脉病(PAD)。CAD是美国死亡的主要原因,研究将血管发生的缺陷与CAD的发展相联系(例如,Matsunaga等人,Am J Physiol Heart CircPhysiol 288:H2042-H2046,2005)。动物局部缺血模型中的研究表示,施用生血管生长因子可以增强新血管形成的营养灌流。在晚期CAD患者的治疗性血管发生的临床实验中,使用生长因子例如VEGF和FGF,显示了运动时间的增加和心绞痛症状的减轻。血管发生还表现出改善了心肌梗塞后的血流(Takeshita等人,J.Clin.Invest.93:662-670,1994)。因此,血生血管因子是治疗血管疾病的有希望的治疗剂。
[0008]然而,迄今为止,尚未完全阐述清楚FGF21在癌症和血管疾病中的角色。因此,需要鉴定调节FGF21的组合物和方法。本发明是针对上述以及其它重要的需要。
[000129]同源性还可以在多肽水平。在一些实施方案中,多肽与SEQ IDNO:2或其部分至少约85%、约90%、约92%、约94%、约95%、约97%、约98%、约99%和约100%同源。在一些实施方案中,多肽具有多达5个、多达10个、多达15个、多达20个或多达30个氨基酸插入、缺失或取代。
[000149]本发明还提供用于治疗、抑制和管理血管病症或疾病的方法和组合物,所述病症或疾病对于现有的或标准治疗已经部分或完全抗拒。
[000159]在一些实施方案中,抗体是人源化抗体。人源化抗体可以通过多种方法实现,包括例如:(1)将非人互补决定区(CDR)移植到人构架区和恒定区(本领域称为“人源化”的过程),或可选的(2)移植整个非人可变结构域,但通过替换表面残基用人-类似表面“隐匿(cloaking)”它们(本领域称为“镶嵌(veneering)”的过程)。在本发明中,人源化抗体可以包括“人源化的”和“镶嵌的”抗体。类似的,可以通过将人免疫球蛋白基因座引入转基因动物来产生人抗体,例如,内源性免疫球蛋白基因部分或完全失活的小鼠。基于刺激,观察了人抗体生产,其在所有方面都严格模拟在人中观察的,包括基因重排、聚集和抗体谱。该方法描述在例如美国专利号5,545,807、5,545,806、5,569,825、5,625,126、5,633,425、5,661,016和下列科学出版物中:Marks等人,Bio/Technology 10,779-783(1992);Lonberg等人,Nature 368856-859(1994);Morrison,Nature 368,812-13(1994);Fishwild等人,Nature Biotechnology 14,845-51(1996);Neuberger,Nature Biotechnology 14,826(1996);Lonberg和Huszar,Intern.Rev.Immunol.1365-93(1995);Jones等人,Nature 321:522-525(1986);Morrison等人,Proc.Natl.Acad.Sci,U.S.A.,81:6851-6855(1984);Morrison和Oi,Adv.Immunol.,44:65-92(1988);Verhoeyer等人,Science239:1534-1536(1988);Padlan,Molec.Immun.28:489-498(1991);Padlan,Molec.Immunol.31(3):169-217(1994);和Kettleborough,C.A.等人,Protein Eng.4(7):773-83(1991),其每个通过引用整合到本文中。
[000239]本发明还提供了调节患者内FGF21-相关生物学活性的方法。方法包括向患者施用一定量的FGF21调节剂,所述量有效调节一种或多种FGF21生物学活性。在上下文中提出了用于测量FGF21生物学活性的合适测定。