Targeted modified IL-1 family members
The present disclosure relates to a modified Interleukin-1 (IL-1) family member cytokine, with reduced activity via its cytokine receptor, wherein said interleukin-1 family member cytokine is specifically delivered to target cells. Preferably, the IL-1 family member cytokine is a mutant, more preferably it is a mutant IL-1 with low affinity to the IL-1 receptor, wherein said mutant IL-1 is specifically delivered to target cells. The targeting is preferably realized by fusion of the modified IL-1 family member cytokine to a targeting moiety, preferably an antibody or antibody-like molecule. The disclosure relates further to the use of such targeted modified IL-1 family member cytokine to treat diseases.
1. A composition comprising a fusion protein comprising:
(1) a mutated human IL-1β cytokine characterized by a reduced activity as compared to wild type human IL-1β cytokine, wherein the mutation is one or more mutations selected from R120G, Q131G, L145A, H146A, L147A, Q148G, F162A, Q164E, and K208E, wherein the numbering is based on the human IL-1β sequence, and
(2) a targeting moiety comprising a variable domain of camelid heavy chain antibodies (VHH), wherein the targeting moiety restores activity of the mutated human IL-1β cytokine on target cells.
2. The composition according to claim 1 , wherein said targeting moiety is directed to a marker expressed on human IL-1β cytokine receptor expressing cell.
3. The composition according to claim 2 , wherein said targeting moiety is directed to a marker expressed on an IL-1R1 and/or IL-1RacP expressing cell.
4. The composition according to claim 1 , wherein the mutated human IL-1β cytokine is characterized by a reduced affinity for its receptor as compared to a wild type human IL-1β cytokine.
5. The composition according to claim 1 , wherein said targeting moiety is directed to a tissue specific marker.
6. The composition according to claim 1 , wherein said targeting moiety is directed to Her2 or leptin receptor.
7. The composition according to claim 1 , wherein the mutated human IL-1β further comprises at least one mutation selected from the group consisting of A117G/P118G, L122A, T125G/L126G, R127G, K132A, S137G/Q138Y, Q148G/Q150G, Q150G/D151A, M152G, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, I172A, V174A, K209A, K209A/K210A, E221K, E221S/N224A, N224S/K225S, E244K and N245Q.
8. The composition according to claim 1 , wherein the mutated human IL-1β comprises Q131G and Q148G.
9. The composition according to claim 8 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.
10. The composition according to claim 1 , wherein the mutated human IL-1β comprises Q148G and K208E.
11. The composition according to claim 10 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.
12. The composition according to claim 1 , wherein the mutated human IL-1β comprises R120G and Q131G.
13. The composition according to claim 12 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.
14. The composition according to claim 1 , wherein the mutated human IL-1β comprises R120G and H146A.
15. The composition according to claim 14 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.
16. The composition according to claim 1 , wherein the mutated human IL-1β comprises R120G and K208E.
17. The composition according to claim 16 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.
18. The composition according to claim 1 , wherein the mutated human IL-1β comprises R120G, F162A, and Q164E.
19. The composition according to claim 18 , wherein the targeting moiety comprises a VHH against HER2 or leptin receptor.