Conjugate comprising an IL-2 moiety
The present invention relates to an IL-2 protein sequence of the formula Ala-SEQ A-Cys*-SEQ B (I), wherein SEQ A has at least 94% sequence identity to SEQ ID NO:1; SEQ B has at least 94% sequence identity to SEQ ID NO:2; Ala is an alanine residue; and Cys* is a cysteine residue; to conjugates thereof and their uses in the treatment of cancer.
1. A conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1d)
is conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod , being stable, and to which IL-2 moiety a moiety of formula (XI-a)
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible.
2. The conjugate or pharmaceutically acceptable salt thereof of claim 1 , wherein b2 is 2.
3. The conjugate or pharmaceutically acceptable salt thereof of claim 1 , wherein b2 is 3.
4. The conjugate or pharmaceutically acceptable salt thereof of claim 1 , wherein b3 is an integer ranging from about 100 to 125.
5. The conjugate or pharmaceutically acceptable salt thereof of claim 1 , wherein p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
6. The conjugate or pharmaceutically acceptable salt thereof of claim 1 , wherein b2 is 2, b3 is an integer ranging from about 100 to 125 and p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
7. A conjugate or pharmaceutically acceptable salt thereof, the conjugate comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1e)
is conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod being stable, and to which IL-2 moiety a moiety of formula (XI-a)
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible.
8. The conjugate or pharmaceutically acceptable salt thereof of claim 7 , wherein b2 is 2.
9. The conjugate or pharmaceutically acceptable salt thereof of claim 7 , wherein b2 is 3.
10. The conjugate or pharmaceutically acceptable salt thereof of claim 7 , wherein b3 is an integer ranging from about 100 to 125.
11. The conjugate or pharmaceutically acceptable salt thereof of claim 7 , wherein p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
12. The conjugate or pharmaceutically acceptable salt thereof of claim 7 , wherein b2 is 2, b3 is an integer ranging from about 100 to 125 and p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
13. A conjugate or pharmaceutically acceptable salt thereof comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1a)
is conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod being stable, and to which IL-2 moiety a moiety of formula (XI-a)
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible.
14. The conjugate or pharmaceutically acceptable salt thereof of claim 13 , wherein b2 is 2.
15. The conjugate or pharmaceutically acceptable salt thereof of claim 13 , wherein b2 is 3.
16. The conjugate or pharmaceutically acceptable salt thereof of claim 13 , wherein b3 is an integer ranging from about 100 to 125.
17. The conjugate or pharmaceutically acceptable salt thereof of claim 13 , wherein p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
18. The conjugate or pharmaceutically acceptable salt thereof of claim 13 , wherein b2 is 2, b3 is an integer ranging from about 100 to 125 and p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
19. A mixture comprising
(i) at least one conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1d)
is stably conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod being stable, and to which IL-2 moiety a moiety of formula (XI-a)
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible; and
(ii) at least one conjugate or a pharmaceutically acceptable salt thereof, the conjugate comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1e)
is conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod being stable, and to which IL-2 moiety a moiety of formula (XI-a)
(XI-a),
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible.
20. The mixture of claim 19 , wherein b2 of formula (A-1d) and formula (A-1e) is 2.
21. The mixture of claim 19 , wherein b2 of formula (A-1d) and formula (A-1e) is 3.
22. The mixture of claim 19 , wherein b3 of formula (A-1d) and formula (A-1e) is an integer ranging from about 100 to 125.
23. The mixture of claim 19 , wherein each of p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
24. The mixture of claim 19 , wherein each b2 is 2, each b3 is an integer ranging from about 100 to 125 and each of p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
25. The mixture of claim 19 , further comprising one or more conjugates or pharmaceutically acceptable salts thereof comprising an IL-2 moiety of SEQ ID NO:14, to which a moiety M mod of formula (A-1a)
is conjugated to the sulfur of the cysteine at position 38, wherein the dashed line marked with the asterisk indicates attachment to the sulfur and wherein b1 is 2, b2 is 2 or 3 and b3 is an integer wherein the molecular weight of M mod is 5±25% kDa, the conjugation to M mod being stable, and to which IL-2 moiety a moiety of formula (XI-a)
is conjugated to the nitrogen of a primary amine of the N-terminus or a lysine side chain residue of the IL-2 moiety; wherein the dashed line indicates attachment to the nitrogen and p1, p2, p3 and p4 are independently of each other an integer ranging from 185 to 450, the conjugation to the moiety of formula (XI-a) being reversible.
26. The mixture of claim 25 , wherein b2 of formulas (A-1d), (A-1e) and (A-1a) is 2.
27. The mixture of claim 25 , wherein b2 of formulas (A-1d), (A-1e) and (A-1a) is 3.
28. The mixture of claim 25 , wherein b3 of formulas (A-1d), (A-1e) and (A-1a) is an integer ranging from about 100 to 125.
29. The mixture of claim 25 , wherein each of p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.
30. The mixture of claim 25 , wherein each b2 is 2, each b3 is an integer ranging from about 100 to 125 and each of p1, p2, p3 and p4 are independently of each other an integer ranging from 220 to 240.