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(12) Patent Application Publication (10) Pub. No.: US 2015/0018530 A1 Miao Et Al US 201500 18530A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0018530 A1 Miao et al. (43) Pub. Date: Jan. 15, 2015 (54) NOVEL PRODRUG CONTAINING Related U.S. Application Data MOLECULE COMPOSITIONS AND THEIR (60) Provisional application No. 61/605,072, filed on Feb. USES 29, 2012, provisional application No. 61/656,981, (71) Applicant: Ambrx, Inc., La Jolla, CA (US) filed on Jun. 7, 2012. (72) Inventors: Zhenwei Miao, San Diego, CA (US); Publication Classification Ho Sung Cho, San Diego, CA (US); Bruce E. Kimmel, Leesburg, VA (US) (51) Int. Cl. A647/48 (2006.01) (73) Assignee: AMBRX, INC., La Jolla, CA (US) C07K 6/28 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/381,196 CPC ....... A6IK 47/48715 (2013.01); C07K 16/2896 (2013.01); A61K 47/48215 (2013.01); A61 K (22) PCT Fled: Feb. 28, 2013 47/48284 (2013.01); A61K 47/48384 (2013.01) USPC ....................................................... 530/387.3 (86) PCT NO.: PCT/US2O13/028332 S371 (c)(1), (57) ABSTRACT (2) Date: Aug. 26, 2014 Novel prodrug compositions and uses thereof are provided. Patent Application Publication Jan. 15, 2015 Sheet 1 of 21 US 201S/0018530 A1 FIGURE 1. Antigen recognition site Hinge Peptide Patent Application Publication Jan. 15, 2015 Sheet 2 of 21 US 2015/0018530 A1 FIGURE 2 M C7 leader VH(108) (GGGGS)4 VL(108) Y96xs His A. ( +PEG ) His 144 Tyr190 Lys248 Ser136am (+PEG) Leu156 B. 6X His VH(108) (GGGGS)4 VL(108) H, is Leu156 g3 ST lear VL (108) Ck(hu) VH(108) CH1(hu) 6X His - SD L I (AA SP re A Lys 142 am Thr204 am Lys219 am Patent Application Publication Jan. 15, 2015 Sheet 3 of 21 US 201S/0018530 A1 FIGURE 3 A. B. Suppression. Western Purification: Coomassie pAF -- - - - - - - - - - - - - - Ara -- + - Growth LB media LB media Super broth media media Construct: WT scFw-108 ScFW-108-S13 An (GlySer2) Patent Application Publication Jan. 15, 2015 Sheet 4 of 21 US 2015/0018530 A1 FIGURE 4 :::::::::::: . E.is . SCFV-108-L156 Am WT SCFV-108 Patent Application Publication Jan. 15, 2015 Sheet 5 of 21 US 2015/0018530 A1 FIGURE 5 is:3::::::::::::: Patent Application Publication Jan. 15, 2015 Sheet 6 of 21 US 2015/0018530 A1 FIGURE 6 A. 35000 30000 25000 20000 - 15000 - 10000 5000 - e-11 le-1 0 1 e-9 le-7 le-6 le-5 Wt scF W108 C. 35000 50000 45000 30000 4OOOO 35000 25000 s 3OOOO c 20000 a 25000 20000 15000 15000 "1e-11 le-10 le-9 le-8 le-7 le-6 le-5 le-11 le-10 le-9 le-8 le-7 le-6 le-5 scFv108 Ser136pAF scFw 108 Ser136pAF-5K PEG IC50=13.1 nM, r2=0.997 IC50=51 nM, r2=0,990 Patent Application Publication Jan. 15, 2015 Sheet 7 of 21 US 201S/0018530 A1 FIGURE 7 800 600 400 200 1e-12 1e-11 1e-10 1e-9 1e-8 1e-7 1e-6 1e-5 Fab 108 EC50=3 nM, r2=0.990 800 600 400 200 1e-12 1e-11 1e-10 1e-9 1e-8 1e-7 1 e-6 1e-5 Fab 108 T204pAF EC50=6.2 nM, r2=0.998 Patent Application Publication Jan. 15, 2015 Sheet 8 of 21 US 201S/0018530 A1 FIGURE 8 Biparatropic Antibody Model for ErbB2 Pertuzumab ErbB2 (Omnitarg) Herceptin Light Chain -s?- (Trastuzumab) Patent Application Publication Jan. 15, 2015 Sheet 9 of 21 US 201S/0018530 A1 FIGURE 9 scFv-toxin Conjugate and Release O -- O conjugation ma-e- required Non-naturally for activity encoded amino acid Camptothecin X is a linker to control the drug release Patent Application Publication Jan. 15, 2015 Sheet 10 of 21 US 201S/0018530 A1 FIGURE 10 Reactive Reactive group A group B A. SNOMor) L SNOMonon Patent Application Publication Jan. 15, 2015 Sheet 11 of 21 US 201S/0018530 A1 FIGURE 11 Prodrug + PEGylation Patent Application Publication Jan. 15, 2015 Sheet 12 of 21 US 201S/0018530 A1 FIGURE 12 Prodrug Strategies Using Non-Naturally Encoded Amino Acids N. 7-O. O e LP. sN 1 2 "e Nye) N-NHa O HO R. X = O, NH, NMe Patent Application Publication Jan. 15, 2015 Sheet 13 of 21 US 201S/0018530 A1 FIGURE 3 Prodrug + Albumin Conjugate - -s-X mimo Modification HS aAx' GLP-O Conjugation S-S aAx - GLP-O R N Controlled release Patent Application Publication Jan. 15, 2015 Sheet 14 of 21 US 201S/0018530 A1 FIGURE 14 A Dual Cleavage Prodrug Linker X = O, NH Y = CH, O, NH Patent Application Publication Jan. 15, 2015 Sheet 15 of 21 US 201S/0018530 A1 FIGURE 15 S-X NH O NJ)n + H. Y GD Antibod H nx'y () Antibod HN-V carrierntibody protein-COOH or -- HN-Vicarrier1 CIOOCy protein-COOH Or Y=X = O,Q, NH, SCH2 n = 1, 2 The drug release rate is controllable by different combinations of X, Y, and n. Patent Application Publication Jan. 15, 2015 Sheet 16 of 21 US 201S/0018530 A1 FIGURE 16 NO pAF2 -i : conjugation H inactive H scFw-toxin conjugate CM R controlled release anato required for activity Camptothecin Patent Application Publication Jan. 15, 2015 Sheet 17 of 21 US 2015/0018530 A1 FIGURE 17 Glucose-Triggered insulin Release After meal The polymer-insulin payload (l) is prepared from a functional polymer (I) conjugated with modified insulin molecules (ge) through a special chemistry, which triggers controlled-release of insulin dependent on the blood glucose () concentrations with/without meals. Patent Application Publication Jan. 15, 2015 Sheet 18 of 21 US 201S/0018530 A1 FIGURE 182 Aryl Boronic Acid Esters 1. Chemistry: "The stability of boronic ester is determined by the diol used in the polymers, the substitution (X) of the aryl boronic acid, and the Concentration of blood glucose and other sugars. 2. Polymer: oH PEG or PEG grafted polymers to be functionalized with proper diolor 1. equivalent able to form relatively stable boronic esters with insulin. OH Examples of diols: OH OH OH X H / ou OH / O OH uC N OH O Patent Application Publication Jan. 15, 2015 Sheet 19 of 21 US 201S/0018530 A1 FIGURE 18 3. Insulin: & Lt. OH p H CHOH pH CHNHCH A. Incorporation of non-naturally HO1 B HO B HO B encoded amino acids (I-III) into insulin (AX-ins). In this category, OH OH OH the non-naturally encoded amino HN HN HN acids may be incorporated into any O O desired position of insulin, B. Modifying the B chain N-terminal terminal Phe with an aryl boronic s acid moiety (X-ins, IV). HO O H N N H C. Modifying the B chain Lys29 V with an ary boronic acid moiety (X-ins). Patent Application Publication Jan. 15, 2015 Sheet 20 of 21 US 201S/0018530 A1 FIGURE 19 Strategy II: Oxo Hemiacetal 1. Chemistry: 3ru-OHO r R s H 2. Polymer: PEG or PEG grafted polymers to be functionalized with proper Sugarloyclic hemiacetal Or equivalent able to form relatively stable COValent bond with oxoamine derived insulin. Patent Application Publication Jan. 15, 2015 Sheet 21 of 21 US 201S/0018530 A1 FIGURE 19 continued 3. Insulin: QMe O g. HT N N A. Incorporation of non-naturally H encoded amino acids (l-Ill) into () insulin (AX-ins). In this OH ^-oh HN OH Category, the non-naturally encoded amino acid Could be incorporated into any desired III position of insulin. B. Modifying the B chain N- OWe terminal Phe with an HN oxoamine moiety (X-lins, IV). B1 l O H H O1 NH NH C. MOdifvind the B chain LVS29 with an oxoamineying moiety (X-y So- N ins, V,VI). V O US 2015/0018530 A1 Jan. 15, 2015 NOVEL PRODRUG CONTAINING tiers in Cancer Chemotherapy, 317-338, ACS Symposium MOLECULE COMPOSITIONS AND THEIR Series 796; and I.Ojima etal eds, American Chemical Society USES 2001. Cytotoxic drugs such as methotrexate, daunorubicin, doxorubicin, Vincristine, vinblastine, melphalan, mitomycin FIELD OF THE INVENTION C. chlorambucil, calicheamicin and maytansinoids have been conjugated to a variety of murine monoclonal antibodies. In 0001. This invention relates to novel prodrug containing Some cases, the drug molecules were linked to the antibody molecules (PDCMs) wherein the PDCMs comprise one or molecules through an intermediary carrier molecule Such as more polypeptides containing at least one non-naturally-en serum albumin Garnett et al., 46 Cancer Res. 2407-2412 coded amino acid. The present invention relates generally to (1986); Ohkawa et al., 23 Cancer Immunol. Immunother. the field of the production and selection of polypeptides for 81-86 (1986); Endo etal, 47 Cancer Res. 1076-1080 (1980), PDCMs by the methods of molecular biology, using chemis dextran Hurwitz et al., 2 Appl. Biochem. 25-35 (1980); try along with recombinant DNA techniques. Manabi et al., 34 Biochem. Pharmacol. 289-291 (1985); Dillman et al., 46 Cancer Res. 4886-4891 (1986); and Shoval BACKGROUND OF THE INVENTION etal, 85 Proc. Natl. Acad. Sci. U.S.A. 8276-8280 (1988), or 0002 Therapeutic molecules such as those described polyglutamic acid Tsukada et al. 73 J. Natl. Canc. Inst. herein are referred to as prodrug containing molecules 721-729 (1984); Kato et al., 27 J. Med. Chem. 1602-1607 (PDCM). PDCMs comprise one or more polypeptides con (1984); Tsukada et al., 52 Br. J. Cancer 111-116 (1985)}. A taining at least one non-naturally-encoded amino acid. wide array of linkers is available for the preparation of such 0003 Prodrugs include, but are not limited to, chemical immunoconjugates, including both cleavable and non-cleav derivatives of a biologically-active parent compound which, able linkers.
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