Immunomodulatory polynucleotides and uses thereof
Provided are immunomodulatory polynucleotides with sequences of SEQ ID NOs:1-12 which are TLR9 agonists. Therapeutic combinations comprising the immunomodulatory polynucleotides are provided too.
1. An immunomodulatory polynucleotide, comprising a sequence selected from the group consisting of: SEQ ID NO.: 1, SEQ ID NO.: 2, SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, SEQ ID NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ ID NO.: 10, SEQ ID NO.: 11, and SEQ ID NO.: 12.
2. The immunomodulatory polynucleotide of claim 1 , wherein said polynucleotide comprises a chemical modification.
3. The immunomodulatory polynucleotide of claim 1 , wherein said polynucleotide comprises a modification of one or more phosphate groups.
4. The immunomodulatory polynucleotide of claim 3 , wherein said modification of one or more phosphate groups is a phosphorothioate linkage.
5. The immunomodulatory polynucleotide of claim 3 , wherein phosphate backbone of said polynucleotide is completely phosphorothioate-modified.
6. The immunomodulatory polynucleotide of claim 3 , wherein the modification of one or more phosphate group is a linkage.
7. A method of modulating an immune response in a subject, comprising: administering to a subject an immunomodulatory polynucleotide selected from the group consisting of: SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 11, in an amount sufficient to modulate an immune response in said individual.
8. A therapeutic combination, comprising:
(i) an effective amount of a targeted therapeutic against a cancer; and
(ii) an effective amount of an immunomodulatory polynucleotide according to claim 1 , or a combination thereof.
9. The combination of claim 8 , wherein said targeted therapeutic is capable of binding to a tumor cell specifically or preferably in comparison to a non-tumor cell.
10. The combination of claim 9 , wherein said tumor cell is of a carcinoma, a sarcoma, a lymphoma, a myeloma, or a central nervous system cancer.
11. The combination of claim 8 , wherein said targeted therapeutic is capable of binding to a tumor antigen specifically or preferably in comparison to a non-tumor antigen.
12. The combination of claim 11 , wherein said tumor antigen is selected from the group consisting of: CD2, CD19, CD20, CD22, CD27, CD33, CD37, CD38, CD40, CD44, CD47, CD52, CD56, CD70, CD79, and CD137.
13. The combination of claim 11 , wherein said tumor antigen is selected from the group consisting of: 4-1BB, 5T4, AGS-5, AGS-16, Angiopoietin 2, B7.1, B7.2, B7DC, B7H1, B7H2, B7H3, BT-062, BTLA, CAIX, Carcinoembryonic antigen, CTLA4, Cripto, ED-B, ErbB1, ErbB2, ErbB3, ErbB4, EGFL7, EpCAM, EphA2, EphA3, EphB2, FAP, Fibronectin, Folate Receptor, Ganglioside GM3, GD2, glucocorticoid-induced tumor necrosis factor receptor (GITR), gp100, gpA33, GPNMB, ICOS, IGF1R, Integrin αν, Integrin ανβ, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NKGD2, NOTCH, OX40, OX40L, PD-1, PDL1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC44A4, STING (stimulator of IFN genes), Syndecan-1, TACI, TAG-72, Tenascin, TIM3, TRAILR1, TRAILR2, VEGFR-1, VEGFR-2, VEGFR-3, and variants thereof.
14. The combination of claim 8 , wherein said targeted therapeutic comprises an immunoglobulin, a protein, a peptide, a small molecule, a nanoparticle, or a nucleic acid.
15. The combination of claim 8 , wherein said targeted therapeutic comprises an antibody, or a functional fragment thereof.
16. The combination of claim 15 , wherein said antibody is selected from the group consisting of: Rituxan (rituximab), Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (Panitumumab), Arzerra (Ofatumumab), Benlysta (belimumab), Yervoy (ipilimumab), Perjeta (Pertuzumab), Tremelimumab, Opdivo (nivolumab), Dacetuzumab, Urelumab, Tecentriq (atezolizumab, MPDL3280A), Lambrolizumab, Blinatumomab, CT-011, Keytruda (pembrolizumab, MK-3475), BMS-936559, MED14736, MSB0010718C, Imfinzi (durvalumab), Bavencio (avelumab) and margetuximab (MGAH22).
17. The combination of claim 14 , wherein said targeted therapeutic comprises a Fab, Fab′, F(ab′)2, single domain antibody, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibody, minibody, diabody, bispecific antibody fragment, bibody, tribody, sc-diabody, kappa (lamda) body, BiTE, DVD-Ig, SIP, SMIP, DART, or an antibody analogue comprising one or more CDRs.
18. The combination of claim 8 , further comprises a chemotherapeutic agent.
19. The combination of claim 18 , wherein said chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, cytarabine, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide etoposide, gemcitabine, epothilone, vinorelbine, camptothecin, daunorubicin, actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin, or idarubicin.
20. A method for treating a disease condition in a subject that is in need of such treatment, comprising: administering to the subject a composition comprising the immunomodulatory polynucleotide selected from the group consisting of: SEQ ID NO.: 3, SEQ ID NO.: 4, SEQ ID NO.: 5, SEQ ID NO.: 6, and SEQ ID NO.: 11, wherein the disease condition is colorectal cancer, melanoma, or breast cancer.
21. The method of claim 20 , wherein polynucleotide is SEQ ID NO: 6.
22. The method of claim 20 , wherein the polynucleotide comprises a chemical modification.
23. The method of claim 20 , wherein the polynucleotide comprises a modification of one or more phosphate groups.
24. The method of claim 23 , wherein the modification of one or more phosphate groups is a phosphorothioate linkage.
25. The method of claim 23 , wherein the phosphate backbone of the polynucleotide is completely phosphorothioate-modified.
26. The method of claim 20 , wherein the composition further comprises a targeted therapeutic against a cancer.
27. The method of claim 26 , wherein the targeted therapeutic is capable of binding to a tumor cell specifically or preferably in comparison to a non-tumor cell.
28. The method of claim 27 , wherein the tumor cell is of a carcinoma, a sarcoma, a lymphoma, a myeloma, or a central nervous system cancer.
29. The method of claim 26 , wherein the targeted therapeutic is capable of binding to a tumor antigen specifically or preferably in comparison to a non-tumor antigen.
30. The method of claim 29 , wherein the tumor antigen is selected from the group consisting of CD2, CD19, CD20, CD22, CD27, CD33, CD37, CD38, CD40, CD44, CD47, CD52, CD56, CD70, CD79, and CD137.
31. The method of claim 29 , wherein the tumor antigen is selected from the group consisting of 4-1BB, 5T4, AGS-5, AGS-16, Angiopoietin 2, B7.1, B7.2, B7DC, B7H1, B7H2, B7H3, BT-062, BTLA, CAIX, Carcinoembryonic antigen, CTLA4, Cripto, ED-B, ErbB1, ErbB2, ErbB3, ErbB4, EGFL7, EpCAM, EphA2, EphA3, EphB2, FAP, Fibronectin, Folate Receptor, Ganglioside GM3, GD2, glucocorticoid-induced tumor necrosis factor receptor (GITR), gp100, gpA33, GPNMB, ICOS, IGF1R, Integrin αν, Integrin ανβ, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NKGD2, NOTCH, OX40, OX40L, PD-1, PDL1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC44A4, STING (stimulator of IFN genes), Syndecan-1, TACI, TAG-72, Tenascin, TIM3, TRAILR1, TRAILR2, VEGFR-1, VEGFR-2, VEGFR-3, and variants thereof.
32. The method of claim 26 , wherein the targeted therapeutic comprises an immunoglobulin, a protein, a peptide, a small molecule, a nanoparticle, or a nucleic acid.
33. The method of claim 26 , wherein the targeted therapeutic comprises an antibody, or a functional fragment thereof.
34. The method of claim 33 , wherein said antibody is selected from the group consisting of: Rituxan (rituximab), Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (Panitumumab), Arzerra (Ofatumumab), Benlysta (belimumab), Yervoy (ipilimumab), Perjeta (Pertuzumab), Tremelimumab, Opdivo (nivolumab), Dacetuzumab, Urelumab, Tecentriq (atezolizumab, MPDL3280A), Lambrolizumab, Blinatumomab, CT-011, Keytruda (pembrolizumab, MK-3475), BMS-936559, MED14736, MSB0010718C, Imfinzi (durvalumab), Bavencio (avelumab) and margetuximab (MGAH22).
35. The method of claim 32 , wherein said targeted therapeutic comprises a Fab, Fab′, F(ab′)2, single domain antibody, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibody, minibody, diabody, bispecific antibody fragment, bibody, tribody, sc-diabody, kappa (lamda) body, BiTE, DVD-Ig, SIP, SMIP, DART, or an antibody analogue comprising one or more CDRs.
36. The method of claim 26 , wherein the composition further comprises a chemotherapeutic agent.
37. The method of claim 36 , wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, cytarabine, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristine, vinblastine, nocodazole, teniposide etoposide, gemcitabine, epothilone, vinorelbine, camptothecin, daunorubicin, actinomycin D, mitoxantrone, acridine, doxorubicin, epirubicin, or idarubicin.