Immunoconjugates

1. An immunoconjugate comprising

(i) an antibody that binds to Programmed Cell Death Protein 1 (PD-1), wherein the antibody comprises

(a) a heavy chain variable region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:1, a HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, a HVR-H3 comprising the amino acid sequence of SEQ ID NO:3, and a FR-H3 comprising the amino acid sequence of SEQ ID NO:7 at positions 71-73 according to Kabat numbering, and (b) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO:4, a HVR-L2 comprising the amino acid sequence of SEQ ID NO:5, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO:6; or

(b) a heavy chain variable region (VH) comprising a HVR-H1 comprising the amino acid sequence of SEQ ID NO:8, a HVR-H2 comprising the amino acid sequence of SEQ ID NO:9, and a HVR-H3 comprising the amino acid sequence of SEQ ID NO:10, and (b) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO:11, a HVR-L2 comprising the amino acid sequence of SEQ ID NO:12, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO:13; and

(ii) a mutant Interleukin-2 (IL-2) polypeptide comprising the amino acid sequence of SEQ ID NO: 19 with up to five amino acid substitutions, wherein three of said up to five amino acid substitutions are F42A, Y45A and L72G.

2. The immunoconjugate according to claim 1 ,

wherein the antibody comprises (a) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:14, and (b) a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO: 17, and SEQ ID NO:18.

3. The immunoconjugate of claim 1 , wherein the five amino acid substitutions of mutant IL-2 polypeptide are F42A, Y45A, L72G, T3A and C125A.

4. The immunoconjugate of claim 1 , wherein the mutant IL-2 polypeptide comprises the sequence of SEQ ID NO: 20.

5. The immunoconjugate of claim 1 , wherein the immunoconjugate comprises not more than one mutant IL-2 polypeptide.

6. The immunoconjugate of claim 1 , wherein the antibody is an IgG class immunoglobulin.

7. The immunoconjugate of claim 1 , wherein the antibody comprises an Fc domain composed of a first and a second subunit.

8. The immunoconjugate of claim 7 , wherein the Fc domain is an IgG class Fc domain.

9. The immunoconjugate of claim 7 , wherein the Fc domain is a human Fc domain.

10. The immunoconjugate of claim 7 , wherein the Fc domain comprises a modification promoting the association of the first and the second subunit of the Fc domain.

11. The immunoconjugate of claim 7 , wherein in the CH3 domain of the first subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable.

12. The immunoconjugate of claim 7 , wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V) (numberings according to Kabat EU index).

13. The immunoconjugate of claim 12 , wherein in the first subunit of the Fc domain additionally the serine residue at position 354 is replaced with a cysteine residue (S354C) or the glutamic acid residue at position 356 is replaced with a cysteine residue (E356C), and in the second subunit of the Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) (numberings according to Kabat EU index).

14. The immunoconjugate of claim 7 , wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor or reduces effector function.

15. The immunoconjugate of claim 14 , wherein said one or more amino acid substitution is at one or more position selected from the group consisting of L234, L235, and P329 (Kabat EU index numbering).

16. The immunoconjugate of claim 7 , wherein each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A and P329G (Kabat EU index numbering).

17. The immunoconjugate of claim 7 , wherein the mutant IL-2 polypeptide is fused at its amino-terminal amino acid to the carboxy-terminal amino acid of one of the subunits of the Fc domain.

18. The immunoconjugate of claim 17 , wherein the mutant IL-2 polypeptide is fused to the subunit of the Fc domain by a linker peptide, and wherein the linker peptide comprises the amino acid sequence of SEQ ID NO: 21.

19. The immunoconjugate of claim 1 , wherein the mutant IL-2 polypeptide and the antibody are joined by a linker sequence.

20. The immunoconjugate of claim 1 , comprising a polypeptide comprising the sequence of SEQ ID NO:22, a polypeptide comprising the sequence of SEQ ID NO:24, and a polypeptide comprising the sequence of SEQ ID NO:25.

21. A pharmaceutical composition comprising the immunoconjugate of claim 1 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising the immunoconjugate of claim 21 and a pharmaceutically acceptable carrier.

23. The immunoconjugate of claim 1 , comprising a polypeptide comprising the sequence of SEQ ID NO: 22, a polypeptide comprising the sequence of SEQ ID NO: 23, and a polypeptide comprising the sequence of SEQ ID NO: 25.

24. A pharmaceutical composition comprising the immunoconjugate of claim 23 and a pharmaceutically acceptable carrier.

25. The immunoconjugate of claim 1 , wherein

i) the antibody that binds to Programmed Cell Death Protein 1 (PD-1) comprises a heavy chain variable region (VH) comprising a HVR-Hl comprising the amino acid sequence of SEQ ID NO: 1, a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2, a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3, and a FR-H3 comprising the amino acid sequence of SEQ ID NO: 7 at positions 71-73 according to Kabat numbering, and (b) a light chain variable region (VL) comprising a HVR-Ll comprising the amino acid sequence of SEQ ID NO: 4, a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, and

ii) the mutant Interleukin-2 (IL-2) polypeptide comprises the amino acid sequence of SEQ ID NO: 20.

26. The immunoconjugate of claim 25 , wherein the antibody and the mutant IL-2 polypeptide are joined by a linker sequence.

27. A pharmaceutical composition comprising the immunoconjugate of claim 25 and a pharmaceutically acceptable carrier.

28. The immunoconjugate of claim 1 , wherein

i) the antibody that binds to Programmed Cell Death Protein 1 (PD-1) comprises a heavy chain variable region (VH) comprising a HVR-Hl comprising the amino acid sequence of SEQ ID NO: 8, a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 9, and a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10, and (b) a light chain variable region (VL) comprising a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 12, and a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 13, and

ii) the mutant Interleukin-2 (IL-2) polypeptide comprises the amino acid sequence of SEQ ID NO: 20.

29. The immunoconjugate of claim 28 , wherein the antibody and the mutant IL-2 polypeptide are joined by a linker sequence.

30. A pharmaceutical composition comprising the immunoconjugate of claim 29 and a pharmaceutically acceptable carrier.