JPWO2019158914A5 - - Google Patents

Claims (20)

a) at least one of the I421G, T423N, E424S, E450Q or L426Y point mutations of hexon hypervariable region 7 (HVR7 mutation) that interfere with viral binding to coagulation factor 10 (FX);
b) at least one of the S408E or P409A point mutations (KO1 mutations) in the fiber knob region AB loop that prevent viral binding to the coxsackievirus adenovirus receptor ₍ CAR); and c) _αvβ3 / A modified _Ad5 serotype adenovirus containing at least one of the D342E or D342A point mutations in the penton integrin binding motif Arg-Gly-Asp (RGD) that prevents viral binding to the _αVβ5 integrin. 2. The modified adenovirus of claim 1, wherein said HVR7 mutation comprises or consists of at least one of the following point mutations: I421G, T423N, E424S and L426Y. 3. The modified adenovirus of claim 1 or 2, wherein the KO1 mutation comprises or consists of the S408E and P409A point mutations. 4. The modified adenovirus of any one of claims 1-3, wherein the RGD mutation is D342E, resulting in RGE. 5. The modified adenovirus of any one of claims 1-4, wherein the adenovirus is further modified to include at least one cancer-targeting modification or sequence that selectively targets tumor cells. . said adenovirus comprises at least one NGR (containing) peptide motif that binds to aminopeptidase N, wherein said NGR is in the HI loop of the adenoviral fiber protein; or binds to the pan-cancer marker EphA2 at least one YSA (containing) peptide motif, wherein said YSA is in a chimeric fiber, or at least one cancer-targeting antibody, or at least one growth factor antibody, or at least one matrix 6. The modified adenovirus of claim 5 in degradative enzymes. 6. The modified adenovirus of claim 5, wherein said cancer-targeting modification comprises insertion into or expression of the αvβ6 integrin binding peptide or A20 peptide sequence NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1) into or by the virus. 8. The modified adenovirus of claim 7, wherein said A20 peptide sequence is inserted into or expressed in said viral fiber knob HI loop. The adenovirus (Ad5.3D.A20) is
a) at least one of the I421G, T423N, E424S, E450Q or L426Y point mutations of hexon hypervariable region 7 (HVR7 mutation) that interfere with viral binding to coagulation factor 10 (FX);
b) at least one of the S408E or P409A point mutation (KO1 mutation) in the fiber knob region AB loop that prevents viral binding to the coxsackievirus adenovirus receptor (CAR);
c) at least one of the D342E or _{D342A point mutations in the penton integrin binding motif Arg-Gly-Asp (RGD) that prevents viral binding to αVβ3/αVβ5 integrins ; and} d) viral fibers. 9. The modified adenovirus of any one of claims 1-8, comprising insertion or expression of the A20 peptide sequence NAVPNLRGDLQVLAQKVART (SEQ ID NO: 1) in the knob HI loop. A modified adenovirus (Ad5.3D.A20)
a) I421G, T423N, E424S and L426Y point mutations in hexon hypervariable region 7 (HVR7 mutations) that prevent viral binding to coagulation factor 10 (FX);
b) S408E and P409A point mutations (KO1 mutations) in the fiber knob region AB loop that prevent viral binding to the coxsackievirus adenovirus receptor (CAR);
c) a D342E point mutation in the penton integrin binding motif Arg-Gly-Asp (RGD) leading to an RGE mutation that prevents viral binding to αVβ3/αVβ5 integrins; and d) the A20 peptide sequence NAVPNLRGDLQVLAQKVART in the viral fiber knob HI loop ( 9. The modified adenovirus of claim 8, comprising an insertion or expression of SEQ ID NO: 1). 11. The modified adenovirus of any one of claims 1-10, wherein the adenovirus is further modified to contain at least one transgene encoding a therapeutic molecule or drug. 12. The adenovirus of claims 1-11, wherein the adenovirus is further modified to include a 24 base pair deletion dl922-947 (Δ24 mutation) in the E1A gene to restrict viral replication to pRB-deficient cells. Modified adenovirus according to any one of paragraphs. said adenovirus is further modified to contain a single adenine base addition (T1 mutation) at position 445 within the endoplasmic reticulum (ER) retention domain of E3/19K to enhance oncolytic potency; 13. The modified adenovirus according to any one of claims 1-12. 14. A modified adenovirus according to any one of claims 1 to 13 for use as a medicament. 15. A modified adenovirus according to any one of claims 1 to 14 for use in treating cancer. 15. A modified adenovirus according to any one of claims 1 to 14 for use in the manufacture of a medicament for treating cancer. said cancer is nasopharyngeal cancer, synovial cancer, hepatocellular carcinoma, renal cancer, connective tissue cancer, melanoma, lung cancer, intestinal cancer, colon cancer, rectal cancer, colorectal cancer cancer, brain cancer, throat cancer, oral cancer, liver cancer, bone cancer, pancreatic cancer, choriocarcinoma, gastrinoma, pheochromocytoma, prolactinoma, T-cell leukemia/lymphoma , neuroma, von Hippel-Lindau disease, Zollinger-Ellison syndrome, adrenal cancer, anal cancer, bile duct cancer, bladder cancer, ureter cancer, oligodendroglioma, neuroblastoma, meningioma , spinal cord tumor, osteochondroma, chondrosarcoma, Ewing sarcoma, carcinoma of unknown primary, carcinoid, gastrointestinal carcinoid, fibrosarcoma, breast cancer, Paget's disease, cervical cancer , esophageal cancer, gallbladder cancer, head cancer cancer, eye cancer, neck cancer, kidney cancer , Wilms tumor, Kaposi's sarcoma, prostate cancer , testicular cancer, Hodgkin's disease, non-Hodgkin's lymphoma, skin cancer, mesothelioma, multiple myeloma , ovarian cancer, endocrine pancreatic cancer, glucagonoma, parathyroid cancer, penile cancer, pituitary cancer, soft tissue sarcoma, retinoblastoma, small bowel cancer, gastric cancer, thymic cancer, thyroid cancer, villous cancer cancer, hydatidiform mole, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, acoustic neuroma, mycosis fungoides, insulinoma, carcinoid syndrome, somatostatinoma, gingival cancer, heart cancer, lip cancer, meningeal cancer, mouth cancer, nerve cancer, palate cancer, parotid cancer, peritoneal cancer, pharynx cancer, pleural cancer, salivary gland cancer, 17. The modified adenovirus of claim 15 or 16, selected from the group comprising tongue cancer and tonsil cancer. said cancer is ovarian cancer, pancreatic cancer, esophageal cancer, lung cancer, cervical cancer, head and neck cancer, oral cancer, laryngeal cancer, skin cancer, breast cancer, kidney cancer and colorectal cancer 18. The modified adenovirus of claim 17, which is selected from the group comprising cancer. 14. A pharmaceutical composition comprising the modified adenovirus of any one of claims 1-13 and a pharmaceutically acceptable carrier, adjuvant, diluent or excipient. 14. A method of preparing a pharmaceutical composition comprising combining or associating the modified adenovirus of any one of claims 1-13 with a pharmaceutically or veterinary acceptable carrier or vehicle. Method.