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(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 2016/004043 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: gen Road, Newton, Massachusetts 02459 (US). WOOST- C07K 19/00 (2006.01) A61P 35/00 (2006.01) ER, Richard; 6 Buckskin Lane, Natick, Massachusetts A61K 47/48 (2006.01) 01760 (US). BARDER, Timothy; 14 Waldo Road, Arling ton, Massachusetts 02474 (US). WHALEN, Kerry; 2 1 (21) International Application Number: Hillcrest Road, Waltham, Massachusetts 0245 1 (US). GIF- PCT/US2015/038562 FORD, James; 34 Thorndike St., Somerville, Massachu (22) International Filing Date: setts 02144 (US). 30 June 2015 (30.06.2015) (74) Agents: WARD, Donna T. et al; 142A Main Street, Gro- (25) Filing Language: English ton, Massachusetts 01450 (US). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/019,003 30 June 2014 (30.06.2014) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/020,615 3 July 2014 (03.07.2014) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 62/084,306 25 November 2014 (25. 11.2014) u s HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 62/102,261 12 January 20 15 (12.01.2015) u s KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (71) Applicant: BLEND THERAPEUTICS, INC. [US/US]; MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 134 Coolidge Avenue, Watertown, Massachusetts 02472 PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (US). SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors: WHITE, Brian H.; 998 Salem Street, Maiden, Massachusetts 02148 (US). ALARGOVA, Rossitza G.; (84) Designated States (unless otherwise indicated, for every 148 Newton St., Apt.4, Brighton, Massachusetts 02135 kind of regional protection available): ARIPO (BW, GH, (US). BAZINET, Patrick Rosaire; 34 Alpine St, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Somerville, Massachusetts 02144 (US). DUNBAR, Craig TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, A.; 24 Shirley Road, Needham, Massachusetts 02494 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, LEVI SOO, Patrick; 165 Tremont St., Apt 505, Boston, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Massachusetts 021 11 (US). SHINDE, Rajesh R.; 110 Ste LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, arns Hill Rd, Waltham, Massachusetts 0245 1 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, BILODEAU, Mark T.; 227 Border Road, Concord, Mas GW, KM, ML, MR, NE, SN, TD, TG). sachusetts 01742 (US). KADIYALA, Sudhakar; 40 Ha- [Continued on nextpage] (54) Title: TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF 6 2 © 4 ϋ 1 o o © Time h) v (57) Abstract: Particles, including nanoparticles and microparticles, and pharmaceutical formulations thereof, comprising conjug o ates of an active agent such as a therapeutic, prophylactic, or diagnostic agent attached to a targeting moiety via a linker have been designed which can provide improved temporospatial delivery of the active agent and/or improved biodistribution. Methods of mak o ing the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer or infectious diseases. w o 2016/004043 Al II 11 II I 1 Illlll I II II II II III! Ill II I II Published: before the expiration of the time limit for amending the — with international search report (Art. 21(3)) claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) TARGETED CONJUGATES AND PARTICLES AND FORMULATIONS THEREOF REFERENCED TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application No. 62/019,003, filed June 30, 2014, entitled Targeted Conjugates Encapsulated in Particles and Formulations Thereof. U.S. Provisional Patent Application No. 62/020,615, filed July 3, 2014, entitled Particles Incorporating Drug Conjugates of Targeting Scaffolds and Formulations Thereof, U.S. Provisional Patent Application No. 62/084,306, filed November 25, 2014, entitled Targeted Conjugates Encapsulated in Particles and Formulations Thereof, and U.S. Provisional Patent Application No. 62/102,261, filed January 12, 2015, entitled Targeted Conjugates and Particles and Formulations Thereof, the contents of each of which are herein incorporated by reference in their entirety FIELD OF THE INVENTION [0002] This invention is generally in the field of conjugates and particles for drug deliver}'. BACKGROUND OF THE INVENTION [0003 Developments in nanomedicine are generally directed towards improving the pharmaceutical properties of the drags and, in some cases, enhancing the targeted deliver}' in a more cell-specific manner. Several cell-specific drugs have been described, and include monoclonal antibodies, aptamers, peptides, and small molecules. Despite some of the potential advantages of such drags, a number of problems have limited their clinical application, including size, stability, manufacturing cost, immunogenicity, poor pharmacokinetics and other factors. [0004] Nanoparticulate drug delivery systems are attractive for systemic drug delivery because they may be able to prolong the half-life of a . drag in circulation, reduce non-specific uptake of a drug, and improve accumulation of a drug at tumors, e.g., through an enhanced permeation and retention (EPR) effect. There are limited examples of therapeutics formulated for delivery as nanoparticles, which include DOXIL© (liposomal encapsulated doxyrubicin) and ABRAXANE® (albumin bound paclitaxel nanoparticles). [0005] The development of nanotechnologies for effective delivery of drugs or drug candidates to specific diseased cells a d tissues, e.g., to cancer ceils, in specific organs or tissues, in a temporospatially regulated manner potentially can overcome or ameliorate therapeutic challenges such as systemic toxicity. However, while targeting of the delivery system may preferentially deliver drug to a site where therapy is needed, the drug released from the nanoparticle may not for example, remain in the region of the targeted cells in efficacious amounts or may not remain in the circulation in a relatively non-toxic state for a sufficient amount of time to decrease the frequency of treatment or permit a lower amount of drug to be administered while still achieving a therapeutic effect. Accordingly, there is a need in the art for improved drag targeting and delivery, including identification of targeting molecules that can be incorporated into particles and whose presence does not substantially interfere with efficacy of the drug. SUMMARY OF THE INVENTION [0006] Applicants have created molecules that are conjugates of a targeting moiety and an active agent, e.g., a cancer therapeutic agent such as a platinum-containing agent. Furthermore, particles comprising the conjugates are provided. The conjugates can be encapsulated into particles, included in the particle/medium interface, or deposited on the surface of particles. The conjugates and particles are useful for improving the delivery of active agents such as tumor cytotoxic agents to tumor tissue and tumor cells via both passive and active targeting mechanism. [00071 Applicants have developed novel conjugates and particles comprising these conjugates, including polymeric nanoparticles, self-assembling particles, conjugate/surfactant and conjugate/block co-polymers mixed micelles, composite nanoparticles formed by conjugates, surfactants and phospholipids o block c o polymers, or polyaminoacids, or proteins,, inorganic nanoparticles, and pharmaceutical formulations thereof. The conjugates of an active agent such as a therapeutic, prophylactic, or diagnostic agent are attached via a linker to a targeting moiety. The conjugates and particles can provide improved temporospatial delivery of the active agent and/or improved biodistribution compared to deliver)' of the active agent alone. In some cases, the targeting moiety can also act as a therapeutic agent. In some embodiments, the targeting moiety does not substantially interefere with efficacy of the therapeutic agent in vivo. Methods of making conjugates, particles, and formulations comprising such particles are described herein. Such particles are useful for treating or preventing diseases thai are susceptible to the active agent, for example, treating or preventing cancer or infectious diseases. [0008] The conjugates include a targeting ligand and an active agent connected by a linker, wherein the conjugate in some embodiments has the formula: (X -Y Z) wherein X is a targeting moiety; Y is a linker; and Z is an active agent. [0009] One ligand can be conjugated to two or more active agents where the conjugate has the formula: X—(Y—Z) . In other embodiments, one active agent molecule can be linked to two or more ligands wherein the conjugate has the formula: (X Y) Z. n is an integer equal to or greater than 1. [00 ] The targeting moiety, X, may be a molecule such as but not limited to a peptide such as somatostatin, octeotide, LHRH, epidermal growth factor ("EGF"), aptide or bipodal peptide, or RGB-containing peptides, a protein scaffold such as a fibronectin domain,
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    Index Mutated* Normal* FC P value FDR** Probe set Description Gene symbol 113 1342 128 10,52 0,000503 0,240 202018_s_at Lactotransferrin LTF 616 362 46,7 7,76 0,003493 0,308 237395_at Cytochrome P450, family 4, subfamily Z, polypeptide 1 CYP4Z1 3073 1009 142 7,10 0,021674 0,385 206378_at Secretoglobin, family 2A, member 2 SCGB2A2 376 119 17,7 6,68 0,001962 0,284 214451_at Transcription factor AP-2 beta TFAP2B 578 337 60,5 5,57 0,003174 0,300 227702_at Cytochrome P450, family 4, subfamily X, polypeptide 1 CYP4X1 146 210 38,4 5,47 0,000669 0,244 219768_at V-set domain containing T cell activation inhibitor 1 VTCN1 86 129 24,2 5,31 0,000327 0,201 204607_at 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial) HMGCS2 2613 78,7 15,9 4,95 0,017744 0,371 205358_at Glutamate receptor, ionotropic, AMPA 2 GRIA2 116 23,2 4,83 4,81 0,000513 0,240 203908_at Solute carrier family 4, sodium bicarbonate cotransporter, member 4 SLC4A4 117 79,4 18,0 4,42 0,000518 0,240 239723_at Solute carrier family 40 (iron-regulated transporter), member 1 SLC40A1 625 56,6 13,0 4,34 0,003549 0,308 1553394_a_atTranscription factor AP-2 beta TFAP2B 413 148 34,6 4,28 0,002175 0,286 240304_s_at Transmembrane channel-like 5 TMC5 5181 216 50,9 4,25 0,039946 0,421 223864_at Ankyrin repeat domain 30A ANKRD30A 179 446 106 4,21 0,000826 0,244 223315_at Netrin 4 NTN4 246 120 29,2 4,12 0,001128 0,251 210096_at Cytochrome P450, family 4, subfamily B, polypeptide 1 CYP4B1 1043 312 80,2 3,89 0,006080 0,319 204041_at Monoamine oxidase B MAOB 192 44,1 11,6 3,80 0,000899 0,244
  • Evaluation of the Allometric Exponents in Prediction of Human Drug Clearance

    Evaluation of the Allometric Exponents in Prediction of Human Drug Clearance

    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2014 Evaluation of the Allometric Exponents in Prediction of Human Drug Clearance Da Zhang Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Other Pharmacy and Pharmaceutical Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/3533 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ©Da Zhang, 2014 All Rights Reserve EVALUATION OF THE ALLOMETRIC EXPONENTS IN PREDICTION OF HUMAN DRUG CLEARANCE A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By Da Zhang Master of Science, University of Arizona, 2004 Director: F. Douglas Boudinot, Ph.D. Professor, School of Pharmacy, VCU Virginia Commonwealth University Richmond, Virginia August, 2014 ACKNOWLEDGEMENTS First and foremost, I would like to sincerely thank my advisor, Dr. F. Douglas Boudinot, for giving me the opportunity to pursue graduate studies under his guidance and for his continuous professional support, guidance, encouragement and patience throughout my graduate program. He was always delighted in sharing his vast knowledge and kind warmth. I would also like to thank Dr. Ahmad for his scientific advice and support through the complet ion of my degree. He has been a kind and helpful mentor for me. I would like to acknowledge my graduate committee members, Drs.