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(12) Patent Application Publication (10) Pub. No.: US 2010/0068.195 A1 VELLARD Et Al US 2010.0068195A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0068.195 A1 VELLARD et al. (43) Pub. Date: Mar. 18, 2010 (54) MANUFACTURE OF ACTIVE HIGHLY (60) Provisional application No. 61/022,179, filed on Jan. PHOSPHORYLATED HUMAN LYSOSOMAL 18, 2008, provisional application No. 61/099,373, SULFATASE ENZYMES AND USES THEREOF filed on Sep. 23, 2008, provisional application No. 61/110,246, filed on Oct. 31, 2008, provisional appli (75) Inventors: MICHEL C. VELLARD, SAN cation No. 61/226,169, filed on Jul. 16, 2009. RAFAEL, CA (US); VISH KOPPAKA, SAN RAFAEL, CA Publication Classification (US) (51) Int. Cl. Correspondence Address: A638/46 (2006.01) Marshall, Gerstein & Borun (Biomarin) CI2N 9/16 (2006.01) 233 South Wacker Drive, 6300 Sears Tower A6IP 43/00 (2006.01) Chicago, IL 60606 (US) (52) U.S. Cl. ........................................ 424/94.6; 435/196 (73) Assignee: BOMARIN PHARMACEUTICAL INC., (57) ABSTRACT NOVATO, CA (US) This invention provides compositions of active highly phos (21) Appl. No.: 12/629,029 phorylated lysosomal Sulfatase enzymes, their pharmaceuti cal compositions, methods of producing and purifying Such (22) Filed: Dec. 1, 2009 lysosomal Sulfatase enzymes and compositions and their use in the diagnosis, prophylaxis, or treatment of diseases and Related U.S. Application Data conditions, including particularly lysosomal storage diseases (63) Continuation-in-part of application No. 12/355.453, that are caused by, or associated with, a deficiency in the filed on Jan. 16, 2009. lysosomal sulfatase enzyme. HUMAN SULFATASE MODIFYING FACTOR 1 (SUMF1) POLYNUCLEOTIDE SEQUENCE (SEQ ID NO:1) ATGGCTGCGCCCGCACTAGGGCTGGTGTGTGGACGTTGCCCTGAGCTGGGTCTCGTCCTCTTGCTGCTGCTGCTC TCGCTGCTGTGTGGAGCGGCAGGGAGCCAGGAGGCCGGGACCGGTGCGGGCGCGGGGTCCCTTGCGGGTTCTTGC GGCTGCGGCACGCCCCAGCGGCCTGGCGCCCATGGCAGTTCGGCAGCCGCTCACCGATACTCGCGGGAGGCTAAC GCTCCGGGCCCCGTACCCGGAGAGCGGCAACTCGCGCACTCAAAGATGGTCCCCATCCCTGCTGGAGTATTTACA ATGGGCACAGATGATCCTCAGATAAAGCAGGATGGGGAAGCACCTGCGAGGAGAGTTACTATTGATGCCTTTTAC ATGGATGCCTATGAAGTCAGTAATACTGAATTTGAGAAGTTTGTGAACTCAACTGGCTATTTGACAGAGGCTGAG AAGTTTGGCGACTCCTTTGTCTTTGAAGGCATGTTGAGTGAGCAAGTGAAGACCAATATTCAACAGGCAGTTG-CA. GCTGCTCCCTGGTGGTTACCTGTGAAAGGCGCTAACTGGAGACACCCAGAAGGGCCTGACTCTACTATTCTGCAC AGGCCGGATCATCCAGTTCTCCATGTGTCCTGGAATGATGCGGTTGCCTACTGCACTTGGGCAGGGAAGCGGCTG CCCACGGAAGCTGAGTGGGAATACAGCTGTCGAGGAGGCCTGCATAATAGACTTTTCCCCTGGGGCAACAAACTG CAGCCCAAAGGCCAGCATTATGCCAACATTTGGCAGGGCGAGTTTCCGGTGACCAACACTGGTGAGGATGGCTTC CAAGGAACTGCGCCTGTTGATGCCTTCCCTCCCAATGGTTATGGCTTATACAACATAGTGGGGAACGCATGGGAA TGGACTTCAGACTGGTGGACTGTTCATCATTCTGTTGAAGAAACGCTTAACCCAAAAGGTCCCCCTTCTGGGAAA GACCGAGTGAAGAAAGGTGGATCCTACATGTGCCATAGGTCTTATTGTTACAGGTATCGCTGTGCTGCTCGGAGC CAGAACACACCTGATAGCTCTGCTTCGAATCTGGGATTCCGCTGTGCAGCCGACCGCCTGCCCACCATGGACTGA Patent Application Publication Mar. 18, 2010 Sheet 2 of 13 US 2010/0068.195 A1 FIGURE 2 HUMAN SULFATASE MODIFYING FACTOR 1 (SUMF1) POLYPEPTIDE SEQUENCE (SEQ ID NO:2) MAAPALGLVCGRCPELGLVLLLLLLSLLCGAAGSQEAGTGAGAGSLAGSCGCGTPQRPGAHGSSAAAHRYSREAN APGPWPGEROLAHSKMVPIPAGVFTMGTDDPOIKODGEAPARRVTIDAFYMDAYEVSNTEFEKFVNSTGYLTEAE KFGDSFVFEGMLSEQWKTNIQQAVAAAPWWLPVKGANWRHPEGPDSTILHRPDHPVLHVSWNDAVAYCTWAGKRL PTEAEWEYSCRGGLHNRLFPWGNKLOPKGOHYANIWOGEFPVTNTGEDGFOGTAPWDAFPPNGYGLYNIWGNAWE WTSDWWTVHHSVEETLNPKGPPSGKDRVKKGGSYMCHRSYCYRYRCAARSQNTPDSSASNLGFRCAADRLPTMD Patent Application Publication Mar. 18, 2010 Sheet 5 of 13 US 2010/0068.195 A1 FIGURES STRUCTURE AND CHARACTERISTICS OF SECRETED HUMAN N ACETYLGALACTOSAMINE-6-SULFATASE (GALNS) APOPPNILLL LNDDMGWGDL GVY GEPSRET PNLDRMAAEG LLFPNFYSAN PrOCeSSed 51 PCSPSRAAL LTGRLPIRNG FYTTNAHARN AYTPOEIWGG IPDSECLLPE form LLKKAGYWSK IWGKWHIGHR POFHPLKHGF DEWFGSPNCH FGPYDNKARP ~40 KDa 1. NIPVVRDVTEM VGRYY FEFPI NIKTGEA NLT QIYIQEALDF IKRCARHHPF FLY WAWDATH APWYASKPFL GTSQRCRYGD AVREIDDSIG KILELLODLH VADNTFWFFT SDNGAALISA PEOGGSNGPF LCGKQTTFEG GMREPALAWA 1 PGHVTAGOVS HOLGSIMDLF TTSLALAGLT PPSDRAIDGL NLLPTLLCGR LMDRPIFYYR GDTLMAATLG QHKAHFWTWT NSWENFROGI DFCPGCVS ~19 kDa WTTHNLEDHT KLPLIFHLGR DPGERFPLSF ASAEYQEALS RITSVVOCHQ EALVPAOPOL APPGCEKLGK CLTPPESIPK KCLWSH Molecular Weight of pre-processed enzyme. ~ 55kDa Cysteine to CO-formylglycine Conversion at position 53 Processed forms inlySOSome joined by disulfide bridge 2N-linked glycosylation sites at positions 178 and 397 BisP found On ASn178, not on ASn397 Patent Application Publication Mar. 18, 2010 Sheet 6 of 13 US 2010/0068.195 A1 FIGURE 6A {G.I.S.-ye Ce Scree 60 40 s x...it CEN 4A + 3AR i? iiAR if citiA SAF SARS AK Stji FIGURE 6B 4. G.7. S GANS Predactivity s 80. .8 40 2 BHK4A CHO 4A pCNáA+ 8AR A- ifAR A pathia SMF SARS AK Sty Patent Application Publication Mar. 18, 2010 Sheet 7 of 13 US 2010/0068.195 A1 FIGURE 7 LOAD CELL CONTRO Patent Application Publication Mar. 18, 2010 Sheet 8 of 13 US 2010/0068.195 A1 FIGURE 8 WTFBDS WIO NaC 200 175 Ca 150 A A R 04OC 100 AN A. A A A A {) A s A -700C s 76 50 25 O O 20 40 60 80 Days Patent Application Publication Mar. 18, 2010 Sheet 9 of 13 US 2010/0068.195 A1 FIGURE 9A Blue Sepharose 6 FF Chromatography kia 2 3 4 5 i ka 2 3 4 5 & 8 94 3. 8 : s: 64 s S. 3. 39 28 28 ::::::::::::::::: : ::::::::::::::::::::::::::::::::. 8S&S Anti-WA :5000 i3 kef 2. BS 83d 3, 3S 4. BSEq Wash 5, BS Fias 8. 8S f BS Strip FIGURE 9B Fractogel SE Hi-Cap Chromatography ka 2 3 4 5 6 8 3 ka 2 3 4 5 8 9 2. SE ii-Cap lead (807 8 3, SE-i-Cap Wash : 607 4, SE ii-Cap Wash 0 1807 ... SE iii-Cap Eig (807 6, SE Hi-Cap Eia: 0 1687 7, SE Hi-Cap Eu:0: 1607 8, SE-i-Cap Strip (1607 . (se Hi-Cap Strip is07 Cootassie Anti-WA :5309 Patent Application Publication Mar. 18, 2010 Sheet 10 of 13 US 2010/0068.195 A1 FGRE 10 3 : : s 38 28 Coomassie .. Anti-GALNs (1:5000) 3 8 2 3 4 5 Anti-Cathepsin (:00) Anti-CHOR (t: 000) yake 2, it 3. SE Hi-Cap load 04208 4, SE-i-Cap Eitiate (42.08 8, late 4228 8, 3 E38 4248 7. ES 4258 Patent Application Publication Mar. 18, 2010 Sheet 11 of 13 US 2010/0068.195 A1 FIGURE I IDU nM Patent Application Publication Mar. 18, 2010 Sheet 12 of 13 US 2010/0068.195 A1 FIGURE 12 0.000 0.010 0.020 0.030 0.040 0.050 0.060 0.070 ARSB nM Patent Application Publication Mar. 18, 2010 Sheet 13 of 13 US 2010/0068.195 A1 FIGURE 13 -O- Unlabeled -- A488-mal - A - A555-mal O 20 40 60 GALNS nM) US 2010/0068.195 A1 Mar. 18, 2010 MANUFACTURE OF ACTIVE HGHLY 0005 Large-scale production of lysosomal enzymes PHOSPHORYLATED HUMAN LYSOSOMAL involves expression in mammalian cell lines. The goal is the SULFATASE ENZYMES AND USES THEREOF predominant secretion of recombinant enzyme into the Sur rounding growth medium for harvest and processing down CROSS REFERENCE TO RELATED stream. In an ideal system for the large-scale production of APPLICATIONS lysosomal enzymes, enzyme would be efficiently phospho rylated and then directed primarily toward the cell surface 0001. This application claims the benefit of U.S. Provi (i.e., for secretion), rather than primarily to the lysosome. As sional Patent Application No. 61/226,169, filed Jul. 16, 2009. described above, this partitioning of phosphorylated lysoso This application is also a continuation-in-part application of mal enzymes is the exact opposite of what occurs in normal U.S. patent application Ser. No. 12/355.453 filed Jan. 16, cells. Manufacturing cell lines used for lysosomal enzyme 2009, which claims the benefit of U.S. Provisional Patent production focuses on maximizing the level of mannose-6- Application No. 61/022,179, filed Jan. 18, 2008, of U.S. phosphate per mole of enzyme, but is characterized by low Provisional Patent Application No. 61/099,373, filed Sep. 23, specific productivity. In vitro attempts at producing lysoso 2008, and of U.S. Provisional Patent Application No. 61/110, mal enzymes containing high levels of mannose-6-phosphate 246, filed Oct. 31, 2008. moieties have resulted in mixed success (Canfield et al., U.S. Pat. No. 6,537,785). The in vitro enzyme exhibits high levels FIELD OF THE INVENTION ofmannose-6-phosphate, as well as high levels of unmodified terminal mannose. Competition between the mannose-6- 0002 The present invention relates to the technical fields phosphate and mannose receptors for lysosomal enzyme of cellular and molecular biology and medicine, particularly results in the necessity for high doses of enzyme for effec to the manufacture of active highly phosphorylated human tiveness, and could lead to greater immunogenicity to the lysosomal Sulfatase enzymes and their use in the management detriment of the subject being treated. of the lysosomal storage diseases associated with lysosomal 0006 Sulfatases constitute a unique subclass of lysosomal Sulfatase enzyme deficiency. In particular, the present inven enzymes. Sulfatases cleave sulfate esters from a variety of tion relates to the manufacture of active highly phosphory Substrates, including, for example, steroids, carbohydrates, lated recombinant human N-acetylgalactosamine-6-sulfatase proteolgycans and glycolipids. All known eukaryotic sulfa (GALNS) and its use in the management of Mucopolysac tases contain a cysteine residue at their catalytic site. Sulfa charidosis IVa (MPSIVa or Morquio A syndrome) and other tase activity requires post-translational modification of this lysosomal storage diseases associated with a deficiency of cysteine residue to C-formylglycine (FGly). The cysteine to GALNS FGly post-translational enzyme activation occurs within the endoplasmic reticulum on unfolded sulfatases immediately BACKGROUND OF THE INVENTION after translation, prior to targeting of the Sulfatases to the 0003) Lysosomal storage diseases (LSDs) result from the lysosome
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