Methods and compositions involving interleukin-6 receptor alpha-binding single chain variable fragments
View Patent ↗Disclosed are compositions comprising an isolated chimeric interleukin 6 receptor alpha (IL-6Rα) binding protein or cells expressing an isolated chimeric IL-6Rα binding protein. The isolated IL-6Rα chimeric binding protein and cells expressing the protein may be used in methods of treating cancer and reducing the risk of cytokine release syndrome.
1. A method for reducing the risk of cytokine release syndrome in a patient receiving an immunotherapy, the method comprising administering to the patient T cells comprising a heterologous nucleic acid molecule encoding an anti-IL-6Rα single chain antibody variable fragment (scFv) comprising a heavy chain variable region comprising CDR1 (SEQ ID NO:5), CDR2 (SEQ ID NO:6), and CDR3 (SEQ ID NO:7) attached by a heterologous linker to a light chain variable region comprising CDR4 (SEQ ID NO:8), CDR5 (SEQ ID NO:9), and CDR6 (SEQ ID NO:10), wherein the heterologous nucleic acid is expressed in the T cells.
2. The method of claim 1 , wherein the T cells further express a chimeric antigen receptor.
3. The method of claim 2 , wherein the patient has cancer.
4. The method of claim 2 , wherein the patient has or will receive adoptive T-cell therapy.
5. The method of claim 2 , wherein the patient has or will receive lymphodepletion.
6. The method of claim 1 , wherein the T cells are autologous.
7. The method of claim 2 , further comprising administering to the patient an antihistamine, a corticosteroid, a steroid, acetaminophen, furosemide, and/or intravenous fluids.
8. The method of claim 1 , wherein the patient has one or more symptoms of cytokine release syndrome.
9. The method of claim 1 , wherein the heavy chain variable region is on the N-terminal side of the light chain variable region.
10. The method of claim 1 , wherein the light chain variable region is on the N-terminal side of the heavy chain variable region.
11. The method of claim 1 , wherein the linker comprises the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO:11).
12. The method of claim 1 , wherein the heterologous nucleic acid molecule is encoded on an expression construct.
13. The method of claim 12 , wherein the expression construct comprises a cytokine-responsive promoter or promoter that increases expression when T cells are activated.
14. The method of claim 13 , wherein the promoter responds positively to one or more of the following: NFAT-1, NF-κB, IL-6, TNF-α, IFN-γ, IL-1β, IL-2, IL-8, and IL-10.
15. The method of claim 1 , wherein the heterologous nucleic acid further encodes for a signal peptide.
16. The method of claim 1 , wherein the expression construct further comprises a constitutive promoter that controls the expression of the anti-IL-6RαscFv.
17. The method of claim 1 , wherein the patient has an autoimmune disease.
18. The method of claim 12 , wherein the expression construct is further defined as a viral vector.
19. The method of claim 12 , wherein the expression construct is further defined as a plasmid.