1. Technical Field
The present invention relates generally to anti-FN14 antibodies. In particular, the anti-FN14 antibodies described herein are useful for the treatment of diseases, such as a variety of cancers and inflammatory diseases, associated with expression of FN14.
2. Description of the Related Art
The TWEAK protein (gene name TNFSF12), which has also been called CD255 and Apo3L, is a member of the tumor necrosis factor (TNF) family and was isolated in a screen for RNA that hybridized to an erythropoietin probe (Chicheportiche et al., J. Biol. Chem. 272:32401-32410 (1997)). The mouse and human peptides have an unusually high degree of conservation, including 93% amino acid identity in the receptor binding domain. TWEAK, shown to be efficiently secreted from cells, is abundantly expressed in many tissues, including heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, lymph nodes, thymus, appendix, and peripheral blood lymphocytes.
TWEAK has been implicated in many biological processes. For instance, HT29 cells treated with IFN and TWEAK were shown to undergo apoptosis; however, TWEAK's ability to induce apoptosis is weak and only a small number of cell types are susceptible (Chicheportiche et al., J. Biol. Chem. 272:32401-32410 (1997)). In contrast, TWEAK has also been shown to induce angiogenesis and proliferation of endothelial cells in a VEGF-independent pathway (Lynch et al., J. Biol. Chem. 274:8455-8459 (1999)). Astrocytes are specifically bound and stimulated by TWEAK. TWEAK can infiltrate an inflamed brain to influence astrocyte behavior. Astrocytes exposed to TWEAK secrete high levels of IL-6 and IL-8, as well as upregulate ICAM-1 expression (Saas et al., GLIA 32:102-107 (2000)).
FN14 (gene name TNFRSF12A), also known as TWEAKR and CD266, is an inducible TWEAK receptor that is linked to numerous intracellular signaling pathways, including the NF-kB pathway. FN14 has been shown to be induced by FGF, calf serum and phorbol ester treatment and is expressed at relatively high levels in heart, kidney, lung, skin, skeletal muscle, ovary and pancreas tissues, as well as in hepatocellular carcinoma modules and other cancer cell lines, and at lower levels in normal liver tissues. The TWEAK-FN14 signaling pathway appears to play a role in tissue repair and it has been implicated in cancer, chronic autoimmune diseases and acute ischemic stroke (Winkles, J. A. Nature Reviews 7:411 (2008)).
FN14 is a growth factor-regulated immediate-early response gene that decreases cellular adhesion to the extracellular matrix and reduces serum-stimulated growth and migration (Meighan-Mantha et al., J. Biol. Chem. 274:33166-33176 (1999)). FN14 is the smallest member of the TNF receptor superfamily. Proteins in this superfamily are type I transmembrane proteins which belong to one of two subgroups. The first subgroup of proteins contains a death domain motif in the intracellular portion of the protein which interacts with cellular factors that activate the apoptotic pathway (P. W. Dempsey et al, Cytokine Growth Factor Rev 2003; 14:193-209). Proteins in the second subgroup, such as FN14, lack the death domain but possess a domain that interacts with TNF receptor-associated and other cellular factors that regulate a variety of responses including proliferation, differentiation, and in certain cell types, immunoregulatory functions (Bradley J R and Pober J S Oncogene 2001; 20:6482-91). FN14 has a highly conserved 53 amino acid extracellular domain (92.4% identity between mouse and human sequences) and is overexpressed in many but not all tumor types, making it a target of therapeutic interest (Feng, S. L. et al. Am J Pathol 156, 1253-1261 (2000); Han H et al. Cancer Res 62, 2890-2896 (2002); Tran N. L. et al. Am J Pathol 162, 1313-1321 (2003); Watts G. S. et al., Int J Cancer 121, 2132-2139 (2007); Willis A. L. et al., Mol Cancer Res 6, 725-734 (2008)).