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(12) United States Patent (10) Patent No.: US 8,993,295 B2 Seed Et Al

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(12) United States Patent (10) Patent No.: US 8,993,295 B2 Seed Et Al US008993295 B2 (12) United States Patent (10) Patent No.: US 8,993,295 B2 Seed et al. (45) Date of Patent: *Mar. 31, 2015 (54) METHODS, COMPOSITIONS, AND KITS FOR (56) References Cited THE SELECTIVE ACTIVATION OF PROTOXINS THROUGH COMBINATORIAL U.S. PATENT DOCUMENTS TARGETING 4,975,278 A 12/1990 Senter 5,156,840 A 10, 1992 Goers (75) Inventors: Brian Seed, Boston, MA (US); Jia Liu 6,258,360 B1 7/2001 Von Borstel 2002/0142359 A1 10/2002 Copley Wolfe, Winchester, MA (US); Glen S. 2003, OO54000 A1 3/2003 Dowdy Cho, Brookline, MA (US); Chia-Iun 2004/0048784 A1 3/2004 Keener et al. Tsai, Winchester, MA (US) 2009/00 16988 A1* 1/2009 Buckley ....................... 424/85.2 2010/0256070 A1* 10/2010 Seed et al. ................... 514, 19.3 (73) Assignee: The General Hospital Corporation, Boston, MA (US) FOREIGN PATENT DOCUMENTS WO WO98, 20135 A2 5, 1998 (*) Notice: Subject to any disclaimer, the term of this WO WOO1/14570 A1 3, 2001 patent is extended or adjusted under 35 WO WO 2004/094478 A2 11/2004 U.S.C. 154(b) by 1188 days. This patent is Subject to a terminal dis OTHER PUBLICATIONS claimer. Chiron et al. (JBC 272(50):31707-31711 (1997)).* Nygren et al., “Overview of the clinical efficacy of investigational (21) Appl. No.: 12/374,616 anticancer drugs” Journal of Internal Medicine. 253:46-75 (2003). Stenter et al., “Activation of prodrugs by antibody-enzyme conju (22) PCT Fled: Jul. 20, 2007 gates: a new approach to cancer therapy.” The FASEBJournal 4:188 193 (1990). (86) PCT NO.: PCT/US2007/016475 Holliger et al., “Engineered antibody fragments and the rise of single domains.” Nature Biotechnology. 23: 1126-1136 (2005). S371 (c)(1), Hudson et al., “Engineered antibodies' Nature Medicine. 9(1): 129 (2), (4) Date: Nov. 9, 2009 134 (2003). Xu et al. "Strategies for Enzyme/Prodrug Cancer Therapy,” Clinical (87) PCT Pub. No.: WO2O08/O11157 Cancer Research. 7:3314-3324 (2001). Chang et al., “CD13 (aminopeptidase N) can associate with tumor PCT Pub. Date: Jan. 24, 2008 associated antigen L6 and enhance the motility of human lung cancer cells.” Int. J. Cancer. 116:234-252 (2005). (65) Prior Publication Data Melton et al., “The use of prodrugs in targeted anticancer therapies.” S.T.P Pharma Sciences. 9:13-33 (1999). US 201O/OO55761 A1 Mar. 4, 2010 Cortez-Retamozo et al., “Efficient Cancer Therapy with a Nanobody Based Conjugate.” Cancer Research. 64:2853-2857 (2004). Rita Mulherkar, "Gene Therapy for Cancer.” Current Science. Related U.S. Application Data 81(5):555-560 (2001). De Groot et al. "Anticancer Prodrugs for Application in (60) Provisional application No. 60/832,022, filed on Jul. Monotherapy: Targeting Hypoxia, Tumor-Associated Enzymes, and 20, 2006. Receptors.” Current Medicinal Chemistry. 8:1093-1122 (2001). Frankel et al. “Peptide Toxins Directed at the Matrix Dissolution (51) Int. C. Systems of Cancer Cells.” Protein and Peptide Letters(Bentham CI2N 9/96 (2006.01) Science Publishers Ltd.) 9 (1):1-14 (2002). C07K 6/28 (2006.01) (Continued) A6 IK 47/48 (2006.01) B825/00 (2011.01) C07K I4/95 (2006.01) Primary Examiner — Lynn Bristol C07K (4/28 (2006.01) (74) Attorney, Agent, or Firm — Clark & Elbing LLP C07K (4/34 (2006.01) CI2N 9/16 (2006.01) (57) ABSTRACT A61 K38/00 (2006.01) U.S. C. The present invention provides methods and compositions for (52) treating various diseases through selective killing of targeted CPC ....... C07K 16/2803 (2013.01); A61K 47/48561 cells using a combinatorial targeting approach. The invention (2013.01); A61 K47/48715 (2013.01); A61 K features protoxin fusion proteins containing a cell targeting 47/48761 (2013.01); B82Y5/00 (2013.01); moiety and, a modifiable activation moiety which is activated C07K 14/195 (2013.01); C07K 14/28 by an activation moiety not naturally operably found in, on, or (2013.01); C07K 14/34 (2013.01); C12N 9/16 in the vicinity of a target cell. These methods also include the (2013.01); A61 K38/00 (2013.01); C07K combinatorial use of two or more therapeutic agents, at mini 2319/55 (2013.01) mum comprising a protoxin and a protoxin activator, to target USPC .......................................................... 435/188 and destroy a specific cell population. (58) Field of Classification Search USPC .......................................................... 435/188 See application file for complete search history. 17 Claims, 28 Drawing Sheets US 8,993,295 B2 Page 2 (56) References Cited Wels et al., “Construction, bacterial expression and characterization of a bifunctional single-chain antibody-phosphatase fusion protein targeted to the human erbB-2 receptor.” Biotechnology (N.Y.) OTHER PUBLICATIONS 10:1128-1132, 1992. Supplementary European Search Report for European Application Tait et al., “Prourokinase-annexin V Chimeras: Construction, expres No. EP07810652, issued May 7, 2012. sion, and characterization of recombinant proteins. J Biol. Chem. 270:21594-21599, 1995. * cited by examiner U.S. Patent Mar. 31, 2015 Sheet 2 of 28 US 8,993,295 B2 Jaquinu leo empee, Jequinuteo an Ree Jequinu leo ensee equunu Jeo GNgee U.S. Patent US 8,993,295 B2 c s eyedneNee) ©?Infil U.S. Patent US 8,993,295 B2 U.S. Patent US 8,993,295 B2 expedin Hempere U.S. Patent US 8,993,295 B2 9?un61– U.S. Patent Mar. 31, 2015 Sheet 7 of 28 US 8,993,295 B2 £10uu 3d goo-guy . Oue /?Jnfil U.S. Patent Mar. 31, 2015 Sheet 8 of 28 US 8,993,295 B2 s s N ls N t s e s s 8?Jnfil exedin Helengee) U.S. Patent Mar. 31, 2015 Sheet 9 of 28 US 8,993,295 B2 U.S. Patent Mar. 31, 2015 Sheet 10 of 28 US 8,993,295 B2 OL?un61 U.S. Patent US 8,993,295 B2 WGOA-GOO-Que]6oT exedn (Henqee. U.S. Patent US 8,993,295 B2 U.S. Patent US 8,993,295 B2 eyedneApeej €).?un61 U.S. Patent US 8,993,295 B2 eyedn Hempsee U.S. Patent Mar. 31, 2015 Sheet 15 of 28 US 8,993,295 B2 2 S g 9HWSJS) S C 9. OSD 5 S n 9LO-30 CN& CP 9HW-gue C GO-95) ZOO-QUe-LOWu '8 2CO-Qle-O Wul exedn Hewlee. U.S. Patent US 8,993,295 B2 9]©Infil U.S. Patent Mar. 31, 2015 Sheet 17 of 28 US 8,993,295 B2 U.S. Patent US 8,993,295 B2 v upwolf Feo orguooyo 6 U.S. Patent Mar. 31, 2015 Sheet 19 Of 28 US 8,993,295 B2 6]©Infil go so so so 0 wonve 06 08 02 09 09 07 0€. 02 0?. v wra V V ve 0!-- up Wolf eo Ouoo go 9, U.S. Patent Mar. 31, 2015 Sheet 20 of 28 US 8,993,295 B2 OZ?unôl U.S. Patent Mar. 31, 2015 Sheet 21 of 28 US 8,993,295 B2 ********** LZ?un61-3 U.S. Patent US 8,993,295 B2 -AASTAJAJAH-:LQd ZZ?unôl U.S. Patent US 8,993,295 B2 £Z?un61– U.S. Patent Mar. 31, 2015 Sheet 24 of 28 US 8,993,295 B2 U.S. Patent US 8,993,295 B2 U.S. Patent Mar. 31, 2015 Sheet 26 of 28 US 8,993,295 B2 neuneºs 3sequos (GC-ONO'IOES) E 999x19 U.S. Patent US 8,993,295 B2 ZZ?un61 U.S. Patent US 8,993,295 B2 US 8,993,295 B2 1. 2 METHODS, COMPOSITIONS, AND KITS FOR or contributing to the formation of metastases. In those THE SELECTIVE ACTIVATION OF tumors which harbor CSCs it is highly attractive to be able to PROTOXINS THROUGH COMBINATORIAL eliminate these cells. CSCs have been thought to possess TARGETING many properties similar to that of normal stems cells, e.g., long life span, relative mitotic quiescence, and active DNA CROSS-REFERENCE TO RELATED repair capacity, as well as resistance to apoptosis and to drug/ APPLICATIONS toxins through high level expression of ATP-binding cassette drug transporters such as P-glycoprotein. Consequently, This application is the U.S. National Stage of International CSCs are thought to be difficult to target and destroy by Application No. PCT/US2007/16475, filed Jul. 20, 2007, 10 conventional cancer therapies (Dean et al., Nat. Rev. Cancer which in turn, claims the benefit of U.S. Provisional Appli 5:275 (2005)). Conversely, it is critically important to distin cation No. 60/832,022, filed Jul. 20, 2006, each of which is guish CSCs from normal stem cells because of the essential incorporated by reference. roles that normal stem cells play in the renewal of normal tissues. FIELD OF THE INVENTION 15 To increase the selectivity of highly toxic anti-tumor In general, the present invention relates to a therapeutic agents, various attempts have been made to take advantage of strategy for targeting cyotoxic or cytostatic agents to particu specific features of the tumor microenvironment, such as the lar cell types while reducing systemic adverse effects. More low pH, low oxygen tension, or increased density of tumor specifically, the present invention involves the use of a thera specific enzymes, that are not found in the vicinity of normal peutic modality comprising two or more individually inactive cells in well-perfused tissues. Environmentally sensitive anti components with independent targeting principles, which are tumor agents have been developed that are hypothesized to activated through their specific interaction at the targeted exhibit increased toxicity in the solid tumor. For example cells. The invention also provides related methods and com “bioreductive prodrugs are agents that can be activated to positions.
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