AGONIST FUSION PROTEIN FOR CD40 AND OX40 AND USES THEREOF

• US 20150368350A1
• Filed: 01/31/2014
• Published: 12/24/2015
• Est. Priority Date: 01/31/2013
• Status: Active Grant

• Current Assignee: Thomas Jefferson University (Main Line Health System)
• Original Assignee: Thomas Jefferson University (Main Line Health System)
• Inventors: Tykocinski, Mark L., Weber, Matthew Charles
• Granted Patent: US 10,533,054 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: C07K 14/70575 NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 NGF C07K14/48, TNF C07K14/525
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Members of the TNF ligand/TNF receptor superfamily play key roles in a large number of biological events. For instance, members of the TNF ligand/TNF receptor superfamily figure prominently in the complex interplay of positive and negative signals that regulate T cell activation, maintenance of T cell effector function, promotion of maturation of antigen-presenting cells, such as dendritic cells, and the T cell stimulation of APCs. TNF receptors are broadly classified in three groups Receptors in the first group contain a death domain in their cytoplasmic tails. Receptors in the second group contain a TRAF interaction motif in their cytoplasmic tails. The third group of TNF receptors do not contain functional intracellular signaling domains but can act as decoy receptors.

Claims

1. A fusion protein comprising Component A and Component B, wherein Component A comprises a polypeptide agonist for OX40 and Component B comprises a polypeptide agonist for CD40, and optionally comprising a linker between Components A and B.

2. The fusion protein of claim 1, wherein the N-terminus of Component A is fused to the C-terminus of Component B, either directly or indirectly via the linker.

3. The fusion protein of claim 1, wherein the N-terminus of Component B is fused to the C-terminus of Component A, either directly or indirectly via the linker.

4. The fusion protein of claim 1, wherein the polypeptide agonist for OX40 comprises at least a portion of the ectodomain of OX40 ligand (OX40L).

5. The fusion protein of claim 1, wherein the polypeptide agonist for OX40 is a derivative of an agonist monoclonal anti-OX40 antibody, the derivative selected from scFvOX40, V_HC_HOX40, and V_HHOX40.

6. The fusion protein of claim 1, wherein the polypeptide agonist for CD40 comprises at least a portion of the ectodomain of CD40 ligand (CD40L).

7. The fusion protein of claim 1, wherein the polypeptide agonist for CD40 is a derivative of an agonist monoclonal anti-CD40 antibody, the derivative selected from scFvCD40, V_HC_HCD40, and V_HHCD40.

8. The fusion protein of claim 4, wherein the ectodomain is from human OX40L.

9. The fusion protein of claim 6, wherein the ectodomain is from human CD40L.

10. The fusion protein of claim 7, wherein the polypeptide agonist for OX40 comprises at least a portion of the ectodomain of OX40L;

and

wherein the N-terminus of Component B is fused to the C-terminus of Component A, either directly or indirectly via the linker.

11. The fusion protein of claim 10, wherein the linker comprises one of SEQ ID NO:

14, SEQ ID NO;

15, or SEQ ID NO;

16.

12. The fusion protein of claim 1 consisting of Component A and Component B, wherein Component A comprises a polypeptide agonist for OX40 and Component B comprises a polypeptide agonist for CD40, and optionally comprising a linker between Components A and B.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1.

14. A method of stimulating the immune system of a patient comprising administering an therapeutically effective amount of the fusion protein of claim 1 to a patient in need of such treatment.

15. The method of claim 14, wherein the administering step further comprises administering a vaccine to the patient.

16. The method of claim 15, wherein the fusion protein and the vaccine are administered simultaneously.

17. The method of claim 15, wherein the fusion protein and the vaccine are administered sequentially.

18. A method of treating a proliferative disorder in a patient comprising administering a therapeutically effective amount of the fusion protein of claim 1 to a patient in need of such treatment.

19. The method of claim 18, wherein the proliferative disorder is cancer.

20. The method of claim 19, wherein the cancer is one of a hematological B cell malignancy and melanoma.

21. A method of treating a persistent viral infection in a patient comprising administering an therapeutically effective amount of the fusion protein of claim 1 to a patient in need of such treatment.

22. The method of claim 21, wherein the persistent viral infection is one of chronic hepatitis, herpes virus-induced disease, and HIV/AIDS.

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1, for use in stimulating the immune system of a patient in need of such treatment.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1, for use in treating a proliferative disorder.

25. The pharmaceutical composition of claim 24, wherein the proliferative disorder is cancer.

26. The pharmaceutical composition of claim 25, wherein the cancer is one of a hematological B cell malignancy and melanoma.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the fusion protein of claim 1, for use in treating a persistent viral infection.

28. The pharmaceutical composition of claim 27, wherein the persistent viral infection is one of chronic hepatitis, herpes virus-induced disease, and HIV/AIDS.