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WO 2017/031114 Al 23 February 2017 (23.02.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/031114 Al 23 February 2017 (23.02.2017) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12N 9/16 (2006.01) A61K 38/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/US20 16/047 166 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 16 August 2016 (16.08.2016) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 62/206,001 17 August 2015 (17.08.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: ALEXION PHARMACEUTICALS, INC. TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, [US/US]; 100 College St., New Haven, CT 06510 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: JALURIA, Pratik; 35 Bridle Path Lane, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Madison, CT 06443 (US). SUI, Siguang; 413 Juniper GW, KM, ML, MR, NE, SN, TD, TG). Lane, Cheshire, CT 06410 (US). Published: (74) Agents: ARMSTRONG, Todd et al; Clark & Elbing LLP, 101 Federal Street, 15th Fllor, Boston, MA 021 10 — with international search report (Art. 21(3)) (US). — with sequence listing part of description (Rule 5.2(a)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: MANUFACTURING OF ALKALINE PHOSPHATASES (57) Abstract: A method for producing a recombinant polypeptide, comprising: (a) providing a 100L to 25,000 L fed-batch bioreactor comprising (i) cells capable of expressing the recombinant polypeptide as- fotase alfa (SEQ ID NO: 1), and (ii) a cul ture medium suitable for conducting such expression, the culture medium comprising about 25 µΜ to about 300 µ,Μ zinc; (b) culturing the cells under conditions suitable to express the recombinant asfotase alfa wherein the pH of the culture medium is about 6,7 to about 7.1, and wherein zinc is added into said culture medium such that the zinc concentration in the culture medi um is maintained at a concentration of about 25 µΜ to about 300 µΜ of zinc. [001] The amino acid sequences listed in the accompanying sequence listing are shown using standard three-letter code for amino acids, as defined in 37 C.F.R. 1.822. The Sequence Listing is submitted as an ASCII text file, created on August 16, 2016, named 0351 WO_SL.txt and 6,604 bytes in size, which is incoiporated by reference herein. FIELD OF THE INVENTION [002] The disclosure is directed to a method for producing a recombinant polypeptide, comprising: (a) providing a 100L to 25,000 L fed-batch bioreactor comprising (i) cells capable of expressing the recombinant polypeptide asfotase alfa (SEQ ID NO: 1), and (ii) a culture medium suitable for conducting such expression, the culture medium comprising about 25 µΜ to about 300 µΜ zinc; (b) culturing the cells under conditions suitable to express the recombinant asfotase alfa, wherein the pH of the culture medium is about 6.7 to about 7.1, and wherein zinc is added into said culture medium such that the zinc concentration in the culture medium is maintained at a concentration of about 25 µΜ to about 300 µΜ of zinc. BACKGROUND [003] Hypophosphatasia (HPP) is a life-threatening, genetic and ultra-rare metabolic disorder that results i a failure to produce functional tissue nonspecific alkaline phosphatase (TNSALP) It leads to the accumulation of unmineraiized bone matrix (e.g. rickets, osteomalacia), characterized by hypo-mineralization of bones and teeth. When growing bone does not mineralize properly, an impairment of growth is a result that disfigures joints and bones. This result in turn impacts motor performance, respiratory function, and may even lead to death. Different forms of HPP were discovered to include perinatal, infantile, juvenile, and adult HPP. Recently, six clinical forms have been defined, most based upon age at symptom onset, to include perinatal, benign prenatal, infantile, juvenile, adult, and odonto-HPP. Asfotase alfa is an approved first-in-class targeted enzyme replacement therapy designed to address defective endogenous TNSALP levels. For treating HPP with TNSALP, see Whyte et a ., 2012 N Engl J Med. 366:904-13. [004] Asfotase alfa (STRENSIQ®, Alexion Pharmaceuticals, Inc.) is a soluble fusion glycoprotein comprised of the catalytic domain of human TNSALP, a human immunoglobulin Gl Fc domain and a deca aspartate peptide (i.e., D10) used as a bone-targeting domain. In vitro, asfotase alfa binds with a greater affinity to hydroxyapatite than does soluble TNSALP lacking the deca-aspartate peptide, thus allowing the TNSALP moiety of asfotase alfa to efficiently degrade excess local inorganic pyrophosphate (PPi) and restore normal mineralization. Pyrophosphate hydrolysis promotes bone mineralization, and its effects are similar among the species evaluated in nonclinical studies. Initial efficacy studies were conducted in a mouse model of HPP {Akp2 '~mice). The Akp2~ mouse model, created by inactivating the TNSALP gene (Narisawa et al. 9Ί Dev Dyn. 208 :432-46), shares many common features of the human condition including accumulation of unmineralized bone matrix. BRIEF SUMMARY [005] Disclosed herein are compositions of alkaline phosphatases (e.g., asfotase alfa) which have specific characteristics (e.g., particular glycan structures, particular total sialic acid content (TSAC) values, etc.) and manufacturing processes utilized to produce the alkaline phosphatases (e.g., asfotase alfa) having such specific characteristics. Such alkaline phosphatases (e.g., asfotase alfa) are suited for use in therapy, for example, for treatment of conditions associated with decreased alkaline phosphatase protein levels and/or functions (e.g., insufficient cleavage of inorganic pyrophosphate (PPi)) in a subject, for example, a human subj ect [006] In one aspect, the present disclosure provides a method for producing a recombinant polypeptide having alkaline phosphatase function. In various embodiments, the alkaline phosphatase function may include any functions of alkaline phosphatase known in the art, such as enzymatic activity toward natural substrates including phosphoethanolamine (PEA), inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP). Such recombinant polypeptide can comprise asfotase alpha (SEQ ID NO: I). [007] In some embodiments, the method disclosed herein further comprises adding zinc into said culture medium for producing the recombinant polypeptide. Zinc may help improving the activity and/or stability of the recombinant polypeptide. In some embodiments, zinc may be added to provide a zinc concentation of from about I to about 300 µΜ in said culture medium. In one embodiment, zinc may be added to provide a zinc concentation of from about 0 to about 150 µΜ (e.g., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 µΜ) in the culture medium. I some embodiments, zince is added to provide a zinc concentration in the culture medium of from about 25 µΜ to about 150 µΜ, or about 60 µΜ to about 150 µΜ . In one particular embodiment, zinc is added to provide a zinc concentration in the culture medium of from about about 30, 60, or 90 µΜ of zinc. In one particular embodiment, zinc is added to provide a zinc concentration in the culture medium of about 28 µΜ . In some embodiments, the zinc is added into said culture medium in a bolus, continuously, or semi -continuously. [008] In some embodiments, the method disclosed herein further comprises controlling the p of said culture medium for producing the recombinant polypeptide. For example, the pH may be set at about 6.8 to about 7.0. In one particular embodiment, the pH is set at about 6.9. [009J In some embodiments, the method disclosed herein further comprises adding at least one extra fresh culture medium bolus feed to the original cell-containing culture medium during culturing and/or polypeptide production. Such addition of fresh culture medium may improve activity (e.g., specific activity) of the produced recombinant polypeptide. In one embodiment, at least one, two, three, or four feed bolus(es) are added to the culture medium during culturing. In one particular embodiment, at least four feed boluses are added. In some embodiments, the feed bolus addition(s) improves specific activity of the recombinant polypeptide. The cells disclosed herein for producing the recombinant polypeptide may be any cells (e.g., mammalian cells) known in the art. In some embodiments, the ceils are selected from the group comprising CHO, NSO/1, PER.C6, COS-7, human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture), BHK, TM4, CVi, VERO-76, HeLa, MDCK, BRL 3A, W138, Hep G2, MMT 060562, TR , MRC 5, FS4 cells, and Hep G2 cells. In some embodiments, the cells are CHO cells.
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