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WO 2014/043593 A2 O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2014/043593 A2 20 March 2014 (20.03.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 39/02 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 13/059832 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, 13 September 2013 (13.09.201 3) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW. 61/700,663 13 September 2012 (13.09.2012) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: MASSACHUSETTS INSTITUTE OF kind of regional protection available): ARIPO (BW, GH, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, Cambridge, Massachusetts 02139 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: BHATIA, Sangeeta N.; 32 Ingleside Road, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Lexington, Massachusetts 02420 (US). DANINO, Tal; 334 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Harvard Street, Apartment L2, Cambridge, Massachusetts TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 02139 (US). KM, ML, MR, NE, SN, TD, TG). (74) Agent: ZURAWSKI, John A.; Pepper Hamilton LLP, 899 Published: Cassatt Road, 400 Berwyn Park, Berwyn, Pennsylvania 19312 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) < * o (54) Title: PROGRAMMABLE DRUG DELIVERY PROFILES OF TUMOR-TARGETED BACTERIA (57) Abstract: The present invention relates to composition comprising at least one non-pathogenic bacterial cell, wherein the non- pathogenic bacterial cell comprises at least a first and a second nucleic acid sequence, the first nucleic acid sequence comprising at least one non-constitutive promoter operably linked to the second nucleic acid sequence that encodes therapeutic agent, wherein the non-constitutive promoter is an inducible promoter responsive to at least one stimuli and the at least one stimuli comprises the pres - ence of a certain density or a certain number of bacterial cells comprising the first and second nucleic acid sequences. PROGRAMMABLE DRUG DELIVERY PROFILES OF TUMOR-TARGETED BACTERIA CROSS REFERENCE TO RELATED APPLICATIONS This application is PCT Application that claims priority to US Provisional Application Serial No. 61/700,663, filed September 13, 2012, entitled "Programmable Drug Delivery Profiles Of Tumor-Targeted Bacteria, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION This disclosure relates to compositions capable of programmed delivery of therapeutic agents to cancer cells or other cells related to a hyperproliferative disorder in a subject. This disclosure further relates to method of programming at least one bacteria comprising an inducible promoter and a nucleic acid sequence encoding a cellular toxin that modulates the delivery of a therapeutic agent or is itself a therapeutic agent. The bacteria of the invention can be genetically engineered for use in the methods or other aspects of the invention described herein. BACKGROUND OF THE INVENTION The engineering of bacteria to controllably deliver therapeutics is an attractive application for synthetic biology. While most synthetic gene networks have been explored within microbes, there is a need for further characterization of in vivo circuit behavior in the context of applications where the host microbes are actively being investigated for efficacy and safety, such as tumor drug delivery. One major hurdle in is that culture-based selective pressures are absent in vivo, leading to strain-dependent instability of plasmid-based networks over time. Here, we experimentally characterize the dynamics of in vivo plasmid instability using attenuated strains of S. typhimurium and real-time monitoring of luminescent reporters. Computational modeling described the effects of growth rate and dosage on live-imaging signals generated by internal bacterial populations. This understanding will allow us to harness the transient nature of plasmid-based networks to create tunable temporal release profiles that reduce dosage requirements and increase the safety of bacterial therapies. Over the past century, the ability of bacteria to accumulate preferentially in tumors has prompted the investigation of the use of a number of strains for cancer therapy, including C. novyi, E. coli, V. cholorae, B. longum, and S. typhimurium ([3], [12], [2], [24], [15], [21]). Attenuated strains of S. typhimurium have generated particular interest as they can innately home in on tumors and colonize a variety of sizes, and have exhibited safety and tolerance in human clinical trials ([22], [5],[ 1 ],[8]]). S. typhimurium were initially shown to have anti-tumor effects through recruitment of the host immune system and competition with cancer cells for nutrients. Subsequently, engineered production of therapeutic cargo was added through simple genetic modifications. While these studies represent important advances in the use of bacteria for tumor therapies, the majority have relied on constitutive, "always on" cargo production ([9], [23], [14], [6]) that typically results in high dosages, off-target effects, and development of host resistance. As a next step, synthetic biology seeks to add controlled and dynamic production of cargo by utilizing computationally-designed "circuits" that have sophisticated sensing and delivery capability ([7],[4],[17]s[l]). These circuits can be designed to act as delivery systems that sense tumor-specific stimuli and self-regulate cargo production as accessary. Since plasmids are the common framework for synthetic circuits, we begin by characterizing the dynamics of plasmid-based gene expression in vivo by utilizing real time luminescence imaging, quantitative biodistribution measurement, and computational modeling. Together, these approaches provide a framework for exploiting the inherent instability of plasmid-based networks, which will facilitate the generation of specific temporal release profiles directly within the tumor environment. SUMMARY OF THE INVENTION The invention relates to a method of delivering a therapeutic agent to a cancer cell by administering at least one bacterial cell to a subject, the bacterial cell comprising a therapeutic agent operably linked to at least one transcriptional element or promoter, wherein the transcriptional element modulates the expression or secretion of the therapeutic agent in response to the presence of a density or quantity of bacteria comprising the at least one transcriptional element or promoter. In some embodiments, the transcriptional element or promoter is non-constitutive. The invention relates to a composition comprising at least one non-pathogenic bacterial cell, wherein the non-pathogenic bacterial cell comprises at least a first and a second nucleic acid sequence, the first nucleic acid sequence comprising at least one non-constitutive promoter operably linked to the second nucleic acid sequence, the second nucleic acid encoding at least one therapeutic agent, wherein the non-constitutive promoter is an inducible promoter responsive to at least one stimuli and the at least one stimuli comprises the presence of a certain density or a certain number of bacterial cells comprising the first and second nucleic acid sequences. In some embodiments, the composition comprises at least one bacterial cell, wherein the at least one non-pathogenic bacterial cell is chosen from one or a combination of bacterial cells of the genera chosen from: Salmonella, Escherichia, Firmicutes, Bacteroidetes, Lactobacillus, Bifidobacteria, or Acidopholus. In some embodiments, the composition disclosed herein, wherein the bacterial cell comprises no more than five exogenous nucleic acid sequences that are coding sequences, wherein the first exogenous nucleic acid sequence comprises at least one non-constitutive promoter operably linked to the second exogenous nucleic acid sequence that encodes the at least one therapeutic agent. In some embodiments, the invention relates to a composition comprising at least one bacterial cell, wherein the bacterial cell comprises a first, a second, and a third exogenous nucleic acid sequence, wherein the first exogenous nucleic acid sequence comprises at least one inducible promoter, the second exogenous nucleic acid sequence encodes at least one therapeutic agent, and the third exogenous nucleic acid sequence encodes at least one amino acid sequence that directs targeting of the at least one therapeutic to a cancer cell or a cell associated with a hyperprolierative disorder. In some embodiments the promoter is operably linked to the nucleic acid sequence encoding a therapeutic agent and/or to the nucleic acid sequence encoding an amino acid that directs
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