# US 2019/0167737 A1 · Use of iap inhibitor and oncolytic virus in preparation of anti-tumor drug > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0167737 A1 - Document ID: US20190167737A1 - Status: Published application - Kind: A1 - Application number: 16/325,974 - Filed: 2017-08-18 - Published: 2019-06-06 - Earliest claimed: 2016-08-18 - Assignees: Guangzhou Virotech Pharmaceutical Co., Ltd. - Applicants: Guangzhou Virotech Pharmaceutical Co., Ltd. - Inventors: Guangmei YAN; Jing CAI; Yuan LIN; Haipeng ZHANG; Suizhen LIN; Shoufang GONG; Jun HU; Xiao XIAO; Kai LI; Jiankai LIANG; Yaqian TAN; Wenbo ZHU; Wei YIN - Web page: https://patentgrep.com/patent/US20190167737A1 ## CPC - A61K 35/768: Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766 - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)} - A61K 9/7023: {Transdermal patches and similar drug-containing composite devices, e.g. cataplasms (galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006)} - A61K 31/404: Indoles, e.g. pindolol - A61K 31/427: not condensed and containing further heterocyclic rings - A61K 31/713: Double-stranded nucleic acids or oligonucleotides - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Described herein is use of a Caspase activator and an oncolytic virus in the preparation of an anti-tumor drug. As described, Caspase activator can enhance the anti-tumor effect of oncolytic virus, and the combination of Caspase activator and oncolytic virus produces a significant synergistic anti-tumor effect, and demonstrates an effective therapy for the treatment of tumors that are less sensitive to other pharmaceutical treatments. ## Claims ### Claim 1 Use of Caspase activator in the preparation of an anti-tumor synergist for oncolytic virus, wherein the oncolytic virus is selected from at least one alphavirus. ### Claim 2 (depends on 1) The use of claim 1, wherein said alphavirus is at least one selected from the group consisting of M1 virus and Getah virus; preferably, the Caspase activator is at least one selected from the group consisting of Caspase-3, 7, 8, and 9 activators; more preferably, the Caspase activator is a Caspase disinhibitor; more preferably, the Caspase activator is IAP inhibitor; more preferably, the IAP is at least one selected from the group consisting of cIAP-1, cIAP-2 and XIAP. ### Claim 3 (depends on 2) The use of claim 2, wherein the IAP inhibitor is a substance for inhibiting the activity of IAP protein, or a substance for degrading IAP protein, or a genetic tool for reducing the level of IAP protein; preferably, the substance for inhibiting the activity of IAP protein or the substance for degrading IAP protein is selected from the group consisting of a protein or a compound; more preferably, the substance for inhibiting the activity of IAP protein or the substance for degrading IAP protein is selected from Smac protein or a Smac-like compound; or more preferably, the substance for inhibiting the activity of IAP protein or the substance for degrading IAP protein is at least one selected from the group consisting of Smac-like compounds LCL161 and Birinapant; or more preferably, the genetic tool for reducing the level of IAP protein is RNA interference, microRNA, gene editing or gene knock-out material. ### Claim 4 A pharmaceutical composition or a kit, comprising: (a) at least one Caspase activator; and (b) at least one oncolytic virus; the oncolytic virus is selected from at least one alphavirus; preferably, the IAP is at least one selected from the group consisting of cIAP-1, cIAP-2 and XIAP. ### Claim 5 (depends on 4) The pharmaceutical composition or a kit of claim 4, wherein the IAP inhibitor is a substance for inhibiting the activity of IAP protein, a substance for degrading IAP protein, or a genetic tool for reducing the level of IAP protein. ### Claim 6 (depends on 4) The kit of claim 4, wherein the at least one Caspase activator and the at least one oncolytic virus are present as separate components. ### Claim 7 (canceled) ### Claim 8 (depends on 4) The composition or kit according to claim 4, wherein said alphavirus has at least 97.8% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423; preferably, said alphavirus has at least 100% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423. ### Claim 9 (depends on 4) The composition or kit according to claim 4, wherein the tumor is a solid tumor or a blood tumor. ### Claim 10 (depends on 4) The composition or kit according to claim 4, wherein the Caspase activator and oncolytic virus are in a ratio of 0.01 to 15 mg: 103-109 PFU; preferably 0.01-10 mg: 104-109 PFU; more preferably 0.01-10 mg: 105-109 PFU; more preferably, the doses are used as follows: the Caspase activator is used in a range from 0.01 mg/kg to 15 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 103 to 109 (PFU/kg); preferably, the Caspase activator is used in a range from 0.01 mg/kg to 10 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 104 to 109 (PFU/kg); more preferably, the Caspase activator is used in a range from 0.1 mg/kg to 10 mg/kg, while oncolytic virus is used in a titer such that MOI ranges from 105 to 109 (PFU/kg); preferably, said the Caspase activator is LCL161 or Birinapant. ### Claim 11 (depends on 4) The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier; preferably said pharmaceutical composition is in a form of lyophilized powder, injection, tablet, capsule, kit or patch. ### Claim 12 A method for treating a solid or hematological tumor in a subject, comprising: administering to a subject in need thereof at least one oncolytic alphavirus; and at least one Caspase activator, thereby treating the tumor. ### Claim 13 (depends on 12) The method of claim 12, wherein the oncolytic alphavirus is at least one selected from the group consisting of M1 virus and Getah virus; optionally, said M1 virus have a genome as described in Genbank Accession No. EF011023, or have a genome that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, identical to the genomic nucleotide sequence set forth in Genbank Accession No. EF011023; optionally, said Getah virus have a genome as described in Genbank Accession No. EU015062, or have a genome that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, identical to the genomic nucleotide sequence set forth in Genbank Accession No. EU015062; or optionally, said M1 virus has at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423; or optionally, said alphavirus has at least 97.8% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423; more preferably, said alphavirus has at least 100% nucleotide sequence identity to the genome of the M1 virus deposited under Accession No. CCTCC V201423. ### Claim 14 (depends on 12) The method of claim 12, wherein the solid tumor is of a cancer selected from the group consisting of liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, and gastric cancer. ### Claim 15 (depends on 12) The method of claim 12, wherein the LCL161 or Birinapant and alphavirus are provided in a ratio of 0.01 to 15 mg:103-109 PFU. ### Claim 16 (depends on 4) The pharmaceutical composition or the kit according to claim 4, wherein the alphavirus is at least one selected from the group consisting of M1 virus and Getah virus. ### Claim 17 (depends on 4) The pharmaceutical composition or the kit according to claim 4, wherein said Caspase activator is a synthetic Caspase activator; preferably, the Caspase activator is at least one selected from the group consisting of Caspase-3, 7, 8, and 9 activators; more preferably, the Caspase activator is a Caspase disinhibitor. ### Claim 18 (depends on 4) The pharmaceutical composition or the kit according to claim 4, wherein the IAP inhibitor is a protein or a compound; preferably, the IAP inhibitor is selected from the group consisting of Smac protein or a Smac-like compound; preferably, the IAP inhibitor is a compound; more preferably, IAP inhibitor is a compound selected from LCL161 and Birinapant; or more preferably, the genetic tool for reducing the level of IAP protein is RNA interference, microRNA, gene editing or gene knock-out material; preferably, said composition is a composition for treating tumors. ### Claim 19 (depends on 4) The pharmaceutical composition or the kit according to claim 4, wherein said solid tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer; or the tumor is a tumor that is not sensitive to oncolytic virus; preferably, the tumor is liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, or gastric cancer, which is not sensitive to oncolytic virus. ### Claim 20 (depends on 12) The method of claim 12, wherein said Caspase activator is a synthetic Caspase activator; optionally, the caspase activator is a caspase disinhibitor; optionally, the caspase disinhibitor is an IAP inhibitor; optionally, the IAP inhibitor inhibits at least IAP one selected from the group consisting of cIAP-1, cIAP-2 and XIAP; optionally, the IAP inhibitor is an agent that inhibits the activity, degrades, or reduces the expression of IAP protein; optionally, the IAP inhibitor is a peptide, small molecule, or nucleic acid; optionally IAP inhibitor is a SMAC peptide or SMAC-like compound optionally, the SMAC-like compound is LCL161 or Birinapant; optionally, the IAP inhibitor is an RNA interference agent. ### Claim 21 (depends on 12) The method of claim 12, wherein the alphavirus and Caspase inhibitor are provided an a pharmaceutical composition further comprising a pharmaceutically acceptable carrier; preferably, the pharmaceutical composition is formulated as a lyophilized powder, injection, tablet, capsule, kit, or patch.