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  • C12N2710/00011—Details
  • C12N2710/00032—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
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  • C12N2710/00011—Details
  • C12N2710/00041—Use of virus, viral particle or viral elements as a vector
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  • C12N2710/10011—Adenoviridae
  • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
  • C12N2710/10332—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
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  • C12N2710/00011—Details
  • C12N2710/10011—Adenoviridae
  • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
  • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
  • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the Elb-19K insertion site comprises a deletion corresponding to nucleotides 1714-1916 of the Ad5 genome (SEQ ID NO: 1), or the first therapeutic transgene is inserted between nucleotides corresponding to 1713 and 1917 of the Ad5 genome (SEQ ID NO: 1).
• the first therapeutic transgene is inserted between CTGACCTC (SEQ ID NO: 2) and TCACCAGG (SEQ ID NO: 3), e.g., the recombinant adenovirus comprises, in a 5' to 3' orientation, CTGACCTC (SEQ ID NO: 2), the first therapeutic transgene, and
• the E3 insertion site comprises a deletion corresponding to the Ad5 dl309 E3 deletion. In certain embodiments, the E3 insertion site comprises a deletion corresponding to nucleotides 29773-30836 of the Ad5 genome (SEQ ID NO: 1), or the second therapeutic transgene is inserted between nucleotides corresponding to 29773 and 30836 of the Ad5 genome (SEQ ID NO: 1).
• the invention provides a pharmaceutical composition comprising any of the foregoing recombinant adenoviruses and at least one pharmaceutically acceptable carrier or diluent.
• the adenovirus comprises a polynucleotide deletion that results in an adenovirus comprising the sequence CTAGGACTG (SEQ ID NO: 23), AGTGCCCG (SEQ ID NO: 30), or TATTCCCG (SEQ ID NO: 31), which result from joining the two polynucleotide sequences that would otherwise flank the deleted polynucleotide sequence.
• the adenovirus comprises a polynucleotide deletion that results in an adenovirus comprising the sequence TTCCGTGGCG (SEQ ID NO: 32), which results from joining the two polynucleotide sequences that would otherwise flank the deleted polynucleotide sequence.
• the recombinant adenovirus may selectively replicate in a hyperproliferative cell.
• any of the foregoing recombinant adenoviruses may selectively express endostatin and/or angiostatin in a hyperproliferative cell.
• transgene refers to an exogenous gene or polynucleotide sequence.
• therapeutic transgene refers to a transgene, which when replicated and/or expressed in or by the virus imparts a therapeutic effect in a target cell, body fluid, tissue, organ, physiological system, or subject.
• the E3 deletion comprises a deletion of from about 500 to about 1824, from about 500 to about 1500, from about 500 to about 1000, from about 1000 to about 1824, from about 1000 to about 1500, or from about 1500 to about 1824 nucleotides adjacent the stop site of E3-gpl9K.
• the E3 deletion comprises a deletion of about 1600 nucleotides adjacent the stop site of E3-gpl9K. e.g., the E3 deletion comprises a deletion of 1622 nucleotides adjacent the stop site of E3-gpl9K.
• the E3 deletion comprises a deletion corresponding to nucleotides 29218-30839 of the Ad5 genome (SEQ ID NO: 1).
• recombinantly modified enveloped or non-enveloped DNA and RNA viruses preferably selected from baculoviridiae, parvoviridiae, picornoviridiae, herpesviridiae, poxyiridae, or adenoviridiae.
• a recombinantly modified virus is referred to herein as a "recombinant virus.”
• a recombinant virus may, e.g., be modified by recombinant DNA techniques to be replication deficient, conditionally replicating, or replication competent, and/or be modified by
• a recombinant adenovirus comprises a deletion of nucleotides corresponding to -76 to -68 of the adenovirus type 5 Ela promoter, which corresponds to nucleotides 423 to 431 of the Ad5 genome (SEQ ID NO: 1).
• the adenovirus comprises a polynucleotide deletion that results in an adenovirus comprising the sequence TTCCGTGGCG (SEQ ID NO: 32), which results from joining the two polynucleotide sequences that would otherwise flank the deleted polynucleotide sequence.
• An exemplary route of administration is IV infusion.
• Useful formulations can be prepared by methods known in the pharmaceutical art. For example, see Remington's
• compositions preferably are sterile. Sterilization can be
• Exemplary dosing frequencies are once per day, once per week and once every two weeks.
• a preferred route of administration is parenteral, e.g., intravenous infusion.
• the recombinant adenoviruses disclosed herein can be used to treat various medical indications.
• the recombinant adenoviruses can be used to treat cancers.
• the cancer cells are exposed to a therapeutically effective amount of the recombinant adenovirus so as to inhibit or reduce proliferation of the cancer cells.
• the invention provides a method of treating a cancer in a subject.
• solid tumors include malignancies, e.g., sarcomas, adenocarcinomas, and carcinomas, of the various organ systems, such as those affecting head and neck (including pharynx), thyroid, lung (small cell or non-small cell lung carcinoma (NSCLC)), breast, lymphoid, gastrointestinal ⁇ e.g., oral, esophageal, stomach, liver, pancreas, small intestine, colon and rectum, anal canal), genitals and genitourinary tract ⁇ e.g., renal, urothelial, bladder, ovarian, uterine, cervical, endometrial, prostate, testicular), CNS ⁇ e.g., neural or glial cells, e.g., neuroblastoma or glioma), or skin ⁇ e.g., melanoma).
• the cancer is selected from anal cancer, basal cell carcinoma, bladder cancer, bone cancer, brain cancer
• the method comprises administering to the subject an effective amount of a recombinant adenovirus of the invention either alone or in a combination with another therapeutic agent to normalize vasculature in the subject.
• administering an effective amount of a recombinant adenovirus to a subject increases blood flow and/or delivery of oxygen to a tumor in the subject by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
• Vascular normalization can be assayed by methods known in the art, including, e.g., contrast enhanced ultrasound (e.g., dynamic contrast enhanced ultrasound) and FLT-PET.
• angiogenesis-associated disorders include benign tumors, blood-borne tumors, obesity, primary hyperparathyroidism, secondary hype arathyroidism, tertiary
• a nucleotide sequence encoding amino acid residues 1-19 of human plasminogen (corresponding to the signal peptide) followed by residues 97-549 of human plasminogen (corresponding to kringle domains 1-5) is cloned in to the modified Elb-19k region of the TAV-A19k plasmid. All human plasminogen amino acid residue numbers are relative to NCBI Reference Sequence: NP 000292.1, depicted herein as SEQ ID NO: 11.
• the modified plasmid is hereafter referred to as the TAV-hAng plasmid, and any resulting viral particles produced therefrom are hereafter referred to as the TAV-hAng adenovirus.
• the nucleotide sequence of the TAV-hAng plasmid in the Elb-19k region is as follows, where the flanking Elb-19k sequence including the Sail and Xhol restriction sites is underlined:
• the modified plasmid is hereafter referred to as the TAV-Endo-IRES-Ang plasmid, and any resulting viral particles produced therefrom are hereafter referred to as the TAV-Endo-IRES-Ang adenovirus.
• the nucleotide sequence of the TAV-Endo-IRES-Ang plasmid in the Elb-19k region is as follows, where the coding regions are capitalized, the IRES is lowercase, and the flanking Elb-19k sequence including the Sail and Xhol restriction sites is underlined:
• mice Surprisingly for an anti-angiogenic treatment, certain mice showed complete remission in tumor volume, rather than merely a delay in tumor growth. These results are particularly surprising because the effects of bevacizumab are cytostatic rather than cytotoxic.

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• 2018
  • 2018-05-24 EP EP18806701.1A patent/EP3630959A4/en active Pending
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