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(12) Patent Application Publication (10) Pub. No.: US 2014/0004156A1 Mellstedt Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0004156A1 Mellstedt Et Al US 2014.0004156A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0004156A1 Mellstedt et al. (43) Pub. Date: Jan. 2, 2014 (54) BOLOGICAL INHIBITORS OF ROR1 Publication Classification CAPABLE OF INDUCING CELL, DEATH (51) Int. C. (76) Inventors: Hakan Mellstedt, Stockholm (SE): C07K 6/28 (2006.01) Hodjattallah Rabbani, Stockholm (SE); CI2N IS/II3 (2006.01) Ingrid Teige, Lund (SE) (52) U.S. C. CPC ............ C07K 16/28 (2013.01); CI2N 15/1138 (21) Appl. No.: 13/516,925 (2013.01) USPC ...... 424/400; 530/387.9; 536/24.5:536/23.1; (22) PCT Filed: Dec. 10, 2010 435/320.1; 435/325; 435/375; 424/139.1; (86). PCT No.: PCT/EP2010/007524 514/44. A:536/23.53; 435/331 S371 (c)(1), (57) ABSTRACT (2), (4) Date: Mar. 1, 2013 The invention relates to antibodies and siRNA molecules for (30) Foreign Application Priority Data inducing cell death by the specific binding of ROR1, domains thereof of nucleotide molecules encoding ROR1. There are Dec. 18, 2009 (GB) ................................... O922143.3 also provided methods involving and uses of the antibodies Jun. 3, 2010 (GB) ................................... 1OO93O7.8 and siRNA molecules of the invention. Patent Application Publication Jan. 2, 2014 Sheet 1 of 25 US 2014/0004156A1 L/S.*L/SdXL|-WLIXCRIO6] N Patent Application Publication Jan. 2, 2014 Sheet 2 of 25 US 2014/0004156A1 a bi-saw exit-8 ext: xx x: i. s: s x 8. : xxx xx . ex* x8. gri syst {{..} : twic s yxi-xxii. 33. 8 M. : : ised-east x 8. Patent Application Publication Jan. 2, 2014 Sheet 3 of 25 US 2014/0004156A1 8x8 is . sixx 88.888 883 & 8::${ ** $: c: six is: Patent Application Publication Jan. 2, 2014 Sheet 4 of 25 US 2014/0004156A1 | i i O5 O ) O2 to P i Patent Application Publication Jan. 2, 2014 Sheet 5 of 25 US 2014/0004156A1 kD a Progressive Non-Progressive CLL N-ROr1 CO B-actin N-ROr1-46 B-actin C-ROr1-904 B-actin CLL-15 CL-12 CLL-6 CL-8 Control CLL-13 CLL-10 CL-4 CLL-7 Fig. 5 Patent Application Publication Jan. 2, 2014 Sheet 6 of 25 US 2014/0004156A1 isotype control ROr1 Progressive CLL Nums Non-progressive Se Š CLL N o' 10' 0. o 10' 5 Healthy donor O' 10 o 10 Fluorescence intensity Fig. 6 Patent Application Publication Jan. 2, 2014 Sheet 7 of 25 US 2014/0004156A1 o E st 8 O O Z Z kDa M as Extracellular part of a Ror? * recombinant protein 28- . ) 71- ... a sa Intracellular part of a Ror recombinant protein 55 .06 .12.25 0.5 1 2 pig C-ROr1-904 Fig. 7 Patent Application Publication Jan. 2, 2014 Sheet 8 of 25 US 2014/0004156A1 A B -- rs - - . L. d - - - - i. NH- W-in-as-s-s-ad anti-ROr1 Mab PY99 N-ROr Purified activated Purified activated normal B cell normal B cell Fig. 8 Patent Application Publication Jan. 2, 2014 Sheet 9 of 25 US 2014/0004156A1 kDa 111 Fig. 9 Patent Application Publication Jan. 2, 2014 Sheet 10 of 25 US 2014/0004156A1 %| || 2 III. Lll a 2 O O ?o O O. O. O L O D r v c cro N (N v (%) Seo of Ododw Patent Application Publication Jan. 2, 2014 Sheet 11 of 25 US 2014/0004156A1 h O cy 7 / I % II. %525 | 2 (9%) Seo oododv Patent Application Publication Jan. 2, 2014 Sheet 13 of 25 US 2014/0004156A1 NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN Patent Application Publication Jan. 2, 2014 Sheet 14 of 25 US 2014/0004156A1 neg control KNG Fig. 14 Patent Application Publication Jan. 2, 2014 Sheet 15 of 25 US 2014/0004156A1 3 S&SZŽ 2 | | | | O O o O O O O O C. C. C. C. C. C. C. C O O O O O O O O v GN O CO o Q N V Vo V Patent Application Publication Jan. 2, 2014 Sheet 16 of 25 US 2014/0004156A1 -T-I-T-I-T-5 N LILLILLILF NN ILLILLIII: 227 2 NN. N IIIs 2. N.rNN is S. N i % O O O O O OO N CO Vr S. S. Patent Application Publication Jan. 2, 2014 Sheet 20 of 25 US 2014/0004156A1 Patent Application Publication Jan. 2, 2014 Sheet 21 of 25 US 2014/0004156A1 LZ61 Sue/ JOJequnN Patent Application Publication US 2014/0004156A1 Patent Application Publication Jan. 2, 2014 Sheet 23 of 25 US 2014/0004156A1 -09 Ë}08(%) Seo Jo be Patent Application Publication Jan. 2, 2014 Sheet 24 of 25 US 2014/0004156A1 SN (%) AbXOOAO Patent Application Publication Jan. 2, 2014 Sheet 25 of 25 US 2014/0004156A1 GZ-61-I p00npu?S??poq??ueleuO|OOuOUuV-JOXEXIS??L SII00TTOu?360Ae010dx}\/d US 2014/0004156 A1 Jan. 2, 2014 BIOLOGICAL INHIBITORS OF ROR1 derm (Reddy U R et al., Oncogene 1996; 13:1555-9). A CAPABLE OF INDUCING CELL, DEATH shorter transcript from exons 1-7 including a short part of 0001. The present invention relates to biological mol intron 7 has also been described with a predicted length of 393 ecules that inhibit ROR1. In particular there is provided amino acids and a molecular weight of 44 kDa (Ensembl ID: inhibitors such as antibodies and siRNA molecules that are ENSG00000185483). capable of inducing cell death by the specific binding of 0009. In a first aspect of the invention there is provided a ROR1, domains thereof or nucleotide molecules encoding biological inhibitor of ROR1. ROR1. 0010 Biological inhibitors can take many forms and 0002 The work leading to this invention has received include differing modes of action. By Biological inhibition funding from the European Community’s Seventh Frame we mean that the amount of or action of ROR1 is reduced, and work Programme FP7/2007-2013/under grant agreement No may be caused by exposure to a biological inhibitor. For HEALTH-F5-2008-200755. example, the inhibitor may act directly by binding to ROR1 or 0003 Chronic lymphocytic leukaemia (CLL) is a white a nucleotide sequence encoding ROR1. The inhibitor may blood cell cancer that is characterised by an abnormal neo alternatively act by preventing ROR1 interacting with mol plastic proliferation of B lymphocyte cells (B cells). The B ecules that it normally interacts with e.g. by blocking recep cells of CLL differ from normal B cells in their activation and tors, sequestering molecules that bind to or associate with maturation stage and are in particular derived from antigen ROR1, preventing insertion of ROR1 or its binders from experienced B cells with different immunoglobulin heavy inserting into a membrane, such as the cell membrane. chain variable (IgVH) gene mutations (Chiorazzi Net al., N 0011 Preferably, the biological inhibitor binds specifi Engl J Med 2005; 352:804-15). CLL patients with mutated cally to either an extracellular domain of ROR1, an intracel IgVH genes have a better prognosis compared to patients with lular domain of ROR1 or to a nucleotide sequence encoding unmutated genes (Damle RNet al., Blood 1999;94:1840-7: ROR1. Hamblin TJ et al., Blood 1999;94:1848-54). 0012. The biological inhibitor is conveniently one of an 0004 Global gene expression profiling studies have antibody, an interfering nucleic acid molecule or a soluble revealed partly distinguishing but in general overlapping receptor. expression profiles in mutated and unmutated leukaemic B 0013. In one embodiment the biological inhibitor is an cells, Suggesting a common phenotype (Klein Uet al., J Exp antibody. By antibody we mean to complete antibodies and Med 2001; 194:1625-38: Rosenwald A et al., J Exp Med antigen binding fragments thereof. Such fragments are 2001; 194; 1639-47). defined below. 0005 Gene expression profiling studies have shown a 43.8 0014 Antibodies comprise two identical polypeptides of fold increase of the orphan receptor tyrosine kinase (RTK) M, 50,000-70,000 (termed “heavy chains”) that are linked ROR1 in CLL cells (Klein U et al., J Exp Med 2001; 194: together by a disulphide bond, each of which is linked to one 1625-38). Ror1 is a member of the RTK family of orphan of an identical pair of polypeptides of M, 25,000 (termed receptors related to muscle specific kinase (MUSK) and Trk “light chains'). There is considerable sequence variability neurotrophin receptors (Glass DJ, et al., Cell 1996: 85:513 between individual N-termini of heavy chains of different 23; Masiakowski Pet al., J Biol Chem 1992; 267:26181-90; antibody molecules and between individual light chains of Valenzuela D M et al., Neuron 1995; 15:573-84). different antibody molecules and these regions have hence 0006 Ror receptors are cell surface receptors participating been termed “variable domains”. Conversely, there is consid in signal transduction, cell-cell interaction, regulation of cell erable sequence similarity between individual C-termini of proliferation, differentiation, cell metabolism and survival heavy chains of different antibody molecules and between (Masiakowski Petal., Biol Chem 1992: 267:26181-90;Yoda individual light chains of different antibody molecules and A et al., J Recept Signal Transduct Res 2003: 23: 1-15). They these regions have hence been termed "constant domains’. are evolutionarily highly conserved between different species 0015 The antigen-binding site is formed from hyper-vari e.g. human, mouse, Drosophila, and C. elegans. able regions in the variable domains of a pair of heavy and 0007. The human ROR1 gene has a coding region of 2814 light chains. The hyper-variable regions are also known as bp with a predicted 937 amino acids sequence and 105 kDa complementarity-determining regions (CDRS) and deter protein size including an Ig-like domain, cysteine-rich mine the specificity of the antibody for a ligand.
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