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Antibodies to Lrp6

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Antibodies to Lrp6 (19) TZZ¥ __Z___T (11) EP 3 211 011 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 30.08.2017 Bulletin 2017/35 C07K 16/28 (2006.01) (21) Application number: 17153549.5 (22) Date of filing: 14.11.2008 (84) Designated Contracting States: • BINNERTS, Minke AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Francisco, CA 94110 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Carpmaels & Ransford LLP One Southampton Row (30) Priority: 16.11.2007 US 988647 P London WC1B 5HA (GB) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: •Claims filed after the date of receipt of the divisional 08850109.3 / 2 220 247 application (Rule 68(4) EPC). •This application was filed on 27-01-2017 as a (71) Applicant: Nuvelo, Inc. divisional application to the application mentioned San Carlos, CA 94070 (US) under INID code 62. (72) Inventors: • ABO, Arie Oakland, CA 94602 (US) (54) ANTIBODIES TO LRP6 (57) Anti-LRP6 antibodies and antigen-binding frag- ulate Wnt/LRP6 signaling to promote tissue homeosta- ments thereof, as well as pharmaceutical compositions sis, regeneration and repair in diseases such as, but not comprising such antibodies and antigen-binding frag- limited to, bone disorders, such as osteoporosis, rheu- ments are described. These anti-LRP6 antibodies can matoid arthritis, and osteolytic lesions caused by oste- be used to enhance Wnt activity and/or antagonize Dkk1 oarthritis and multiple myeloma, gastrointestinal disease activity. Also described are methods of therapy using and wound healing. suchantibodies and antigen-binding regions tobind mod- EP 3 211 011 A1 Printed by Jouve, 75001 PARIS (FR) EP 3 211 011 A1 Description CROSS-REFERENCE TO PRIOR APPLICATIONS 5 [0001] This application claims the benefit of priority under 35 U.S.C. §119(e)(1) of provisional application serial number 60/998,647 filed November 16, 2007, which application is hereby incorporated by reference in its entirety. TECHNICAL FIELD OF THE INVENTION 10 [0002] The present invention relates to anti-LRP6 antibodies and to binding epitopes of LRP6 used to produce such antibodies. The invention also relates to methods of using such antibodies to diagnose and treat Wnt-associated diseases, such as bone disorders. SEQUENCE LISTING 15 [0003] The sequences of the polynucleotides and polypeptides of the invention are listed in the Sequence Listing and are submitted electronically in the file labeled "NUVO-31PCT_ST25.txt"- 263 KB (269,747 bytes) which was created on an IBM PC, Windows 2000 operating system on October 8, 2008 at 9:06:02 AM. The Sequence Listing entitled "NUVO- 31PCT_ST25.txt" is herein incorporated by reference in its entirety. 20 BACKGROUND OF THE INVENTION [0004] The Wnt/β-catenin cell signaling pathway is implicated in a variety of developmental processes including stem cell maintenance and growth, cellular differentiation, cell growth, oncogenesis and disease pathogenesis (Kirikoshi et 25 al, Int. J. Oncol. 19:767-771 (2001); Munroe et al, Proc. Natl. Acad. Sci. USA 96:1569-1573 (1999); Reya and Clevers, Nature 434:843-850 (2005); Sher et al, FEBS Lett. 522:150-154 (2003)). The activation and regulation of the Wnt/β- catenin pathway therefore appears to be critical for tissue homeostasis, regeneration and repair. The "canonical" Wnt cell signaling pathway has as its central player, the cytosolic protein β-catenin (Figure 1). When Wnt receptors are not engaged, the level of cytosolic β-catenin is kept low through the action of an intracellular complex, known as the "de- 30 struction complex," composed of the tumor suppressor proteins axin and adenomatous polyposis coli (APC) and the serine kinase protein glycogen synthase 3β (GSK3β). The constitutive kinase activity of the destruction complex on β- catenin results in the targeted proteosomal degradation of phosphorylatedβ -catenin. Binding of Wnt to the receptor proteins LRP5 and/or LRP6, members of the LDL receptor family, and Frizzled (FZD), a serpentine receptor, induces phorphorylation-dependent binding of Axin to the LRP6 cytoplasmic tail and recruitment of the cytoplasmic protein 35 Dishevelled (Dvl) to the cytoplasmic tail of FZD, which together lead to the inactivation of theβ-catenin destruction complex. As a consequence, β-catenin accumulates in the cytoplasm and translocates to the nucleus where it is thought to interact with members of the lymphoid enhancer factor (LEF)/T-cell factor (TCF) family of transcription factors and activate target gene expression. [0005] The Wnt coreceptors LRP5/6 are modulated by the secreted ligands Dkk1, Dkk2 and SOST/Sclerostin, a ligand 40 for LRP5/6 and a Wnt signaling inhibitor. Interaction of SOST or Dkk1/2 wth LRP5/6 antagonizes Wnt/ β-catenin signaling. Dkk1 is a high affinity ligand for LRP5/6 and disrupts the formation of the FZD-LRP complex. Dkk1 also binds Kremen- 1 and -2 which are single-pass transmembrane proteins that cooperate with Dkk1 to inhibit Wnt-FZD-LRP6 function. Upon binding of Dkk1 to LRP6 and Kremen-1, receptor complex internalization occurs thereby dampening the Wnt signal due to a decrease of the Wnt coreceptors available for signaling indicating that the cell surface levels of LRP5/6 may 45 limit cellular responses to Wnt ligands (reviewed in He et al, Development 131:1663-1677 (2004) and Semënov et al, J. Biol. Chem. 283:21427-21432 (2008)). [0006] An area in which Wnt signaling has been implicated is the regulation of bone mass in homeostasis and bone disease. Bone mass appears to be influenced by the balance achieved between bone forming cells (osteoblasts) and bone resorbing cells (osteoclasts). Mutations in LRP5 and LRP6 receptors have been reported that either decrease or 50 increase bone density, indicating that the level of Wnt and/or LRP5/6 signaling is critical for maintaining normal bone homeostasis. Consistant with these findings, it has been reported that elevated levels of the LRP5/6 inhibitor Dkk1 in diseases such as rheumatoid arthritis and multiple myeloma, result in osteolytic bone lesions, which can be reversed by Dkk1 antagonists, indicating that Dkk1 may be a regulator of bone density (reviewed in Krishnan et al, J Clin Invest 116:1202-1209 (2006)). 55 [0007] Several studies have also implicated the Wnt signaling pathway in tissue homeostasis and repair in a variety of systems including intestinal, epidermal, and hematopoietic systems. In the intestine, continuous renewal of absorptive epithelium is driven by proliferation of stem cells residing in the intestinal crypts. Current evidence suggests that the Wnt signaling cascade is important in controlling stem cell function in the intestinal crypt since deletion of theβ-catenin- 2 EP 3 211 011 A1 dependent transcription factor TCF4 in mice results in depletion of intestinal crypts and loss of intestinal function (Korinek et al., Nat Genet. 19:379-83 (1998); Barker and Clevers, Nature Rev. 5:997 (2006)). Similarly, overexpression of Dkk1 in the intestine in transgenic mice or in mice injected with adenovirus expressing Dkk1, resulted in a complete loss of crypts in adult mice (Kormek et al, Nature Gen. 19:1-5 (1998); Kuhnert et al., Proc Natl Acad Sci U S A. 101:266-71 5 (2004)). Intestinal diseases, such as inflammatory bowel disease, ulcerative colitis and radiation- or chemotherapy- induced mucositis, are associated with intestinal lesions and loss of intestinal absorptive epithelium, suggesting that modulation of Wnt signaling in intestinal crypts could have therapeutic benefit in treating such diseases. [0008] A similar mechanism of Wnt signaling regulating stem cell function, tissue homeostasis and repair is found in the skin. Hair follicle density and the hair cycle are regulated by Wnt-dependent hair follicle epithelial stem cells (van 10 Genderen et al, Genes Dev. 8:2691-2703 (1994); Lo Celso et al, Development 131:1787-1799 (2004)). Interestingly, the LRP5/6 inhibitor Dkk1 is expressed adjacent to hair follicle buds and over-expression of Dkk1 reduces hair follicle density, indicating that the level of LRP/Wnt signaling is important for regulation of hair follicle density and that Dkk1 may be a regulator of this process (Sick et al., Science. 314:1447-50 (2006)). Recently it was shown that hair follicle stem cells contribute to reepithelialization during wound healing (Ito et al, Nat. Med. 11:1351-4 (2005)), indicating that 15 modulation of Wnt signaling in hair follicle stem cells could be beneficial for wound repair. [0009] In addition to the examples described above, Wnt signaling has also been shown to be important for regulation of stem cells in other tissues and organs, including hematopoietic stem cells (Reya et al, Nature 423:409-414 (2003); Xu et al., Nature Immunol. 4:1177-1182 (2003)), neuronal progenitor stem cells (Zecher et al, Dev. Biol. 258:406-418 (2003)), and even embryonic stem cells (Sato et al, Nature Med. 10:55-63 (2004)) suggesting that modulation of Wnt 20 signaling could also have therapeutic benefits in these systems. [0010] Thus, molecules that modulate Wnt signaling can be useful targets for a broad range of conditions where proliferation, differentiation, tissue regeneration and repair are important to disease processes. The present invention provides anti-LRP6 antibodies that enhance LRP6 activity and antagonize Dkk1 activity for treatment of diseases such as, but not limited to bone disorders such as osteoporosis and osteolytic lesions caused by osteoarthritis and multiple 25 myeloma as well as gastrointestinal disease and wound healing. SUMMARY OF THE INVENTION [0011] The present invention provides isolated antibodies or immunologically functional antibody fragments (i.e. an- 30 tigen-binding fragments) thereof that bind LRP6 epitopes with high affinity and can be used to enhance Wnt signaling and/or antagonize DKK1 activity.
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