Generation of antibodies to tumor antigens and generation of tumor specific complement dependent cytotoxicity by administration of oncolytic vaccinia virus

• US 9,919,047 B2
• Filed: 01/04/2012
• Issued: 03/20/2018
• Est. Priority Date: 01/04/2011
• Status: Active Grant

• Current Assignee: SillaJen, Inc.
• Original Assignee: Sillajen Biotherapeutics Incorporated (SillaJen, Inc.), SillaJen, Inc.
• Inventors: Kirn, David, Bell, John, Breitbach, Caroline, Moon, Anne, Hwang, Tae-Ho, Lee, Yu Kyoung, Kim, Mi-kyung
• Primary Examiner(s): Aeder, Sean E
• Application Number:
  US13/978,113
• Publication Number:
  US 20150037355A1
• Time in Patent Office: 2,267 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 35/26 Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
• CPC Class Codes: A61K 35/76 Viruses; Subviral particles; Bacteriophages
• CPC Class Codes: A61K 35/761 Adenovirus
• CPC Class Codes: A61K 35/763 Herpes virus
• CPC Class Codes: A61K 35/768 Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/001102 Receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: A61K 39/001106 Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
• CPC Class Codes: A61K 39/001164 GTPases, e.g. Ras or Rho
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/125 Picornaviridae, e.g. calicivirus
• CPC Class Codes: A61K 39/145 Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: A61K 39/165 Mumps or measles virus
• CPC Class Codes: A61K 39/17 Newcastle disease virus
• CPC Class Codes: A61K 39/205 Rhabdoviridae, e.g. rabies virus
• CPC Class Codes: A61K 39/235 Adenoviridae
• CPC Class Codes: A61K 39/245 Herpetoviridae, e.g. herpes simplex virus
• CPC Class Codes: A61K 39/285 : Vaccinia virus or variola virus
• CPC Class Codes: A61K 39/395 : Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C12N 2710/10034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/16632 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2710/16634 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/24034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/24132 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2720/12232 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2750/14034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/16034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/18134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/18434 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/18734 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/20034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2760/20232 : Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
• CPC Class Codes: C12N 2770/32034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2770/32334 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2770/36034 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 7/00 : Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00
• CPC Class Codes: G01N 33/574 : for cancer

Abstract

The present invention relates to methods and compositions for use in inducing tumor-specific antibody mediated complement-dependent cytotoxic response in an animal having a tumor comprising administering to said animal a composition comprising a replication competent oncolytic virus wherein administration of the composition induces in the animal production of antibodies that mediate a CDC response specific to said tumor.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of polyclonal complement dependent cytotoxic (CDC)-response producing antibodies specific to multiple tumor cell antigens in an animal and a pharmaceutically acceptable carrier and/or diluent, wherein said composition is produced by a method comprising (a) administering to an animal having a tumor an amount of a composition comprising a replication competent oncolytic vaccinia virus effective to induce polyclonal antibodies in said animal that mediate a CDC response specific to said tumor cell antigens and thereafter (b) obtaining a blood or serum sample from the animal containing said CDC-response producing antibodies and/or B cells producing said antibodies (c) confirming the presence of said antibodies and/or B cells producing said antibodies in said blood or serum sample and (d) isolating CDC-response producing antibodies from said blood or serum, expanding said CDC-response producing antibodies ex vivo or producing CDC-response producing antibodies from said B cells and formulating into a composition, wherein the composition comprises polyclonal antibodies that recognize multiple tumor cell antigens selected from the group consisting of RecQ protein-like (DNA helicase Q1-like) (RECQL);

leptin receptor (LEPR);

ERBB receptor feedback inhibitor 1 (ERRFI1);

lysosomal protein transmembrane 4 alpha (LAPTM4A); and

RAB1B, RAS oncogene family (RAB1B).

2. The composition of claim 1 wherein said oncolytic virus is JX-594.

3. The composition of claim 1 wherein said oncolytic virus comprises a transgene.

4. The composition of claim 3 wherein said heterologous nucleic acid sequence encodes GM-CSF, cytosine deaminase, carboxyl esterase, sodium iodide symporter (NIS), or stomatostatin receptor.

5. The composition of claim 1 wherein said tumor is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, neuroblastoma, pituitary adenoma, medulloblastoma, head and neck cancer, melanoma, prostate carcinoma, renal cell carcinoma, pancreatic cancer, breast cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, liver cancer, bone cancer, rectal cancer, ovarian cancer, sarcoma, gastric cancer, esophageal cancer, cervical cancer, fibrosarcoma, squamous cell carcinoma, neurectodermal, thyroid tumor, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, hepatoma, mesothelioma, epidermoid carcinoma, and tumorigenic diseases of the blood.

6. The composition of claim 1 isolated according to a method comprising isolating CDC-response producing antibodies from said blood or serum.

7. The composition of claim 1 wherein a serum sample is obtained from said subject.

8. A method of inhibiting the growth of or killing a cancer cell comprising contacting said cancer cell with an amount of a composition of claim 1 effective to mediate a CDC-response specific to said cancer cell.

9. The method of claim 8 wherein said contacting comprises contacting cancer cells in vitro with said composition.

10. The method of claim 8 wherein said contacting comprises infusing a subject having cancer with a composition comprising harvested antibodies, harvested B cells, antibodies produced by said harvested B cells or a combination thereof.

11. The method of claim 8 wherein said cancer cell is in vivo in a subject and said contacting comprising administering a medicament comprising said composition.

12. A method of treating a cancer subject comprising administering to said subject an amount of a composition of claim 1 effective to mediate a CDC response to specific to said cancer.

13. The method of claim 12 wherein said composition is autologous to said patient and is isolated from the said cancer patient and reinfused into said cancer patient.

14. The method of claim 12 wherein said composition heterologous to said cancer patient and is isolated from a cancer patient that is different from the cancer patient being treated with said composition.

15. The method of claim 12 wherein said subject is treated with a further anticancer therapeutic agent.

16. The method of claim 12 wherein said cancer subject has as solid tumor and said composition is administered intratumorally, intravenously, intraperitoneally or a combination thereof.

17. The method of claim 16 wherein said cancer subject has a solid tumor that is resected prior to, concurrently or subsequent to administering said composition of claim 6.

18. The method of claim 12 wherein said cancer subject has a solid tumor and said composition reduces the size of the tumor.

19. The method of claim 12 wherein said cancer subject has a solid tumor and said administration reduces metastatic spread of said solid tumor.

20. The method of claim 12 wherein said cancer is selected from the group consisting of astrocytoma, oligodendroglioma, meningioma, neurofibroma, glioblastoma, ependymoma, Schwannoma, neurofibrosarcoma, neuroblastoma, pituitary adenoma, medulloblastoma, head and neck cancer, melanoma, prostate carcinoma, renal cell carcinoma, pancreatic cancer, breast cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, liver cancer, bone cancer, rectal cancer, ovarian cancer, sarcoma, gastric cancer, esophageal cancer, cervical cancer, fibrosarcoma, squamous cell carcinoma, neurectodermal, thyroid tumor, Hodgkin'"'"'s lymphoma, non-Hodgkin'"'"'s lymphoma, hepatoma, mesothelioma, epidermoid carcinoma, and tumorigenic diseases of the blood.

21. The method of claim 18, wherein the tumor is hepatocellular carcinoma.

22. The composition according to claim 1, wherein the animal is a human.

23. The method of claim 15, wherein the further anti-cancer therapeutic agent is sorafenib or sunitinib.

24. A pharmaceutical composition comprising a therapeutically effective amount of polyclonal complement dependent cytotoxic (CDC)-response producing antibodies specific to multiple tumor cell antigens in an animal and a pharmaceutically acceptable carrier and/or diluent, wherein said composition is produced by a method comprising (a) administering to an animal having a tumor an amount of a composition comprising a replication competent oncolytic vaccinia virus effective to induce polyclonal antibodies in said animal that mediate a CDC response specific to said tumor cell antigens and thereafter (b) obtaining a blood or serum sample from the animal containing said CDC-response producing antibodies and/or B cells producing said antibodies (c) confirming the presence of said antibodies and/or B cells producing said antibodies in said blood or serum sample and (d) isolating CDC-response producing antibodies from said blood or serum, expanding said CDC-response producing antibodies ex vivo or producing CDC-response producing antibodies from said B cells and formulating into a composition, wherein the composition comprises polyclonal antibodies that recognize multiple tumor cell antigens selected from the group consisting of RecQ protein-like (DNA helicase Q1-like) (RECQL);

leptin receptor (LEPR);

ERBB receptor feedback inhibitor 1 (ERRFI1);

lysosomal protein transmembrane 4 alpha (LAPTM4A);

RAB1B, RAS oncogene family (RAB1B);

CD24;

homo sapiens thymosin beta 4, X-linked (TMSB4X);

homo sapiens S100 calcium binding protein A6 (S100A6);

homo sapiens adenosine A2 receptor (ADORA2B);

chromosome 16 open reading frame 61 (C16orf61);

ROD1 regulator of differentiation 1 (ROD1);

NAD-dependent deacetylase sirtuin-2 (SIR2L);

tubulin alpha 1c (TUBA1C);

ATPase inhibitory factor 1 (ATPIF1);

stromal antigen 2 (STAG2); and

nuclear casein kinase and cyclin-dependent substrate1 (NUCKS1).