Compositions and methods for tumor-targeted delivery of effector molecules

• US 20040229338A1
• Filed: 12/16/2003
• Published: 11/18/2004
• Est. Priority Date: 10/04/1999
• Status: Abandoned Application

• Current Assignee: Nanotherapeutics, Inc. (National Resilience, Inc.)
• Original Assignee: Vion Pharmaceuticals, Inc.
• Inventors: King, Ivan C.
• Application Number:
  US10/738,423
• Publication Number:
  US 20040229338A1
• Time in Patent Office: Days
• US Class Current: 435/252.3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C12N 15/74 Vectors or expression systems specially adapted for prokaryotic hosts other than E. coli, e.g. Lactobacillus, Micromonospora
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present application discloses the preparation and use of attenuated tumor-targeted bacteria vectors for the delivery of one or more primary effector molecule(s) to the site of a solid tumor. The primary effector molecule(s) of the invention is used in the methods of the invention to treat a solid tumor cancer such as a carcinoma, melanoma, lymphoma, or sarcoma. The invention relates to the surprising discovery that effector molecules, which may be toxic when administered systemically to a host, can be delivered locally to tumors by attenuated tumor-targeted bacteria with reduced toxicity to the host. The application also discloses to the delivery of one or more optional effector molecule(s) (termed secondary effector molecules) which may be delivered by the attenuated tumor-targeted bacteria in conjunction with the primary effector molecule(s).

Claims

1-99. -99. (Canceled)

100. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.

106. The method of claim 100, 101 or 102, wherein at least one of the chemotherapeutic agents is cisplatin, ifosfamide, a taxane, a topoisomerase I inhibitor, gemcitabine, vinorelbine, oxaliplatin, 5-fluorouracil (5-FU), leucovorin, vinorelbine, temodal, cytochalasin B, gramicidin D, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, a glucocorticoid, a puromycin homolog or cytoxan.

107. The method of claim 100, 101 or 102, wherein the attenuated tumor-targeted bacteria is Escherichia coli, Shigella, Yersinia enterocohtica, Listeria monocytogenies, Mycoplasma hominis or Streptococcus.

111. The method of claim 100, 101, 102, 103, 104 or 105, wherein the solid tumor is a tumor of the central nervous system, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, glioma, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma, renal cancer, bladder cancer or mesothelioma.

112. The method of claim 100, 101, 102, 103, 104 or 105, wherein the subject is a human.

101. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.

109. The method of claim 101, 102, 104 or 105, wherein at least one of the primary effector molecules is a TNF family member, anti-angiogenic factor, a tumor inhibitory enzyme, hemolysin, verotoxin, CNF1, CNF2, PMT, or a bacteriocin family member with the proviso said bacteriocin is not BRP.

102. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of one or more chemotherapeutic agents and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules and one or more secondary effector molecule operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is a facultative aerobe or facultative anaerobe.

110. The method of claim 102 or 105, wherein at least one of the secondary effector molecules is an immunomodulating agent, an anti-tumor protein, a pro-drug converting enzyme, an antisense molecule, a ribozyme, an antigen or a bacteriocin release factor.

103. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria, wherein said attenuated tumor-targeted bacteria is Salmonella.

108. The method of claim 103, 104 or 105, wherein the Salmonella is an msbB⁻

Salmonella mutant.

104. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is Salmonella.

105. A method of inhibiting the growth or reducing the volume of a solid tumor cancer, comprising administering to a subject having a solid tumor cancer an effective amount of mitomycin C, cytoxan or cisplatin and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an attenuated tumor-targeted bacteria comprising one or more nucleic acid molecules encoding one or more primary effector molecules and one or more secondary effector molecule operably linked to one or more promoters, wherein said attenuated tumor-targeted bacteria is Salmonella.