Long-acting interleukin-15 receptor agonists and related immunotherapeutic compositions and methods
The instant disclosure provides a long acting IL-15 receptor agonist, related compositions and methods of preparation and use, for example, in the treatment of conditions responsive to therapy effective to provide, for example, sustained immune activation and/or anti-tumor activity.
1. A long-acting interleukin-15 (IL-15) receptor agonist composition comprising a mixture of poly(ethylene glycol)-interleukin-15 moiety conjugates according to Formula (I),
wherein n′ is 1, and
wherein with respect to each of Formula (I) and Formula (II), m is 3, IL-15 is an interleukin-15 moiety, n has a value corresponding to a weight average molecular weight of the poly(ethylene glycol) of about 40,000 daltons, and ˜NH˜ represents an amino group of the IL-15 moiety,
wherein the average number of poly(ethylene glycol) moieties covalently attached to IL-15 amino groups for the conjugates of Formula (I) and Formula (II) comprised in the composition is in a range from 1.0 to about 1.3.
2. The long acting IL-15 receptor agonist composition of claim 1 , comprising no more than about 15 mole percent of the IL-15 conjugates of Formula (II).
3. The long acting IL-15 receptor agonist composition of claim 2 , comprising no more than about 10 mole percent of the IL-15 conjugates of Formula (II).
4. The long acting IL-15 receptor agonist composition of claim 2 , comprising no more than about 7 mole percent of the IL-15 conjugates of Formula (II).
5. The long acting IL-15 receptor agonist composition of claim 2 , comprising no more than about 5 mole percent of the IL-15 conjugates of Formula (II).
6. The long acting IL-15 receptor agonist composition of claim 1 , wherein for the conjugates of Formula (I) and Formula (II) comprised in the composition, the average number of polyethylene glycol moieties covalently attached to IL-15 amino groups is selected from 1.0, 1.1, 1.2 and about 1.3.
7. The long acting IL-15 receptor agonist composition of claim 1 , having an EC50 value (ng/mL, CTLL-2 pSTAT5) that, when compared to the EC50 value (ng/mL, CTLL-2 pSTAT5) of unmodified IL-15, is reduced by no more than about 2-fold.
8. The long acting IL-15 receptor agonist composition of claim 1 , having a receptor alpha binding (KD, pM) value that is reduced by no more than about 50% when compared to IL-15.
9. The long acting IL-15 receptor agonist composition of claim 1 , having a receptor alpha binding (KD, pM) value that is reduced by no more than about 45%, by no more than about 40%, by no more than about 35%, or by no more than about 30% when compared to the receptor alpha binding (KD, pM) value of unmodified IL-15.
10. The long acting IL-15 receptor agonist composition of claim 1 , having an EC50 value (ng/mL, CTLL-2 pSTAT5) that is reduced by no more than about 2-fold when compared to the EC50 value of unmodified IL-15, and having a receptor alpha binding value (KD, pM) that is reduced by no more than about 50% when compared to the receptor alpha binding value (KD, pM) of unmodified IL-15.
11. The long acting IL-15 receptor agonist composition of claim 1 , wherein the conjugates comprised in the composition are less than about 35% deamidated.
12. The long acting IL-15 receptor agonist composition of claim 1 , comprising a mixture of positional isomers of the conjugates according to Formula (I).
13. The long acting IL-15 receptor agonist composition of claim 12 , wherein for the mixture of positional isomers of Formula (I), the amino group is predominantly at the N-terminus of the IL-15 moiety.
14. The long acting IL-15 receptor agonist composition of claim 1 , wherein the IL-15 moiety according to Formula (I) and Formula (II) is a recombinant human IL-15.
15. The long acting IL-15 receptor agonist composition of claim 1 , wherein the IL-15 moiety according to Formula (I) and Formula (II) is unglycosylated.
16. The long acting IL-15 receptor agonist composition of claim 1 , wherein the IL-15 moiety according to Formula (I) and Formula (II) has a sequence having at least about 90% identity to SEQ ID NO:1.
17. The long acting IL-15 receptor agonist composition of claim 1 , wherein the IL-15 moiety according to Formula (I) and Formula (II) has a sequence having at least about 95% identity to SEQ ID NO:1.
18. The long acting IL-15 receptor agonist composition of claim 1 , wherein the IL-15 moiety according to Formula (I) and Formula (II) has a sequence having at least about 99% identity to SEQ ID NO:1.
19. The long acting IL-15 receptor agonist composition of claim 1 comprised in a formulation for parenteral administration.
20. The long acting IL-15 receptor agonist composition of claim 1 , further comprising at least one pharmaceutically acceptable excipient.
21. The long acting IL-15 receptor agonist composition of claim 20 , wherein the pharmaceutically acceptable excipient is a buffer.
22. The long acting IL-15 receptor agonist of claim 21 , wherein the buffer is potassium phosphate.
23. The long acting IL-15 receptor agonist composition of claim 20 , wherein the pharmaceutically acceptable excipient is a carbohydrate.
24. The long acting IL-15 receptor agonist composition of claim 23 , wherein the carbohydrate is trehalose.
25. The long acting IL-15 receptor agonist composition of claim 20 , wherein the pharmaceutically acceptable excipient is a surfactant.
26. The long acting IL-15 receptor agonist composition of claim 25 , wherein the surfactant is polysorbate 20.
27. The long acting IL-15 receptor agonist composition of claim 1 , wherein the composition is comprised in an aqueous medium and has a pH of about 6.5 to 7.0.
28. The long acting IL-15 receptor agonist composition of claim 27 , wherein the composition is comprised in an aqueous medium and has a pH of about 6.8.