CD25-biased anti-IL-2 antibody

1 . A human interleukin-2 (hIL-2)-specific monoclonal antibody (mAb), or antigen-binding fragment thereof, wherein the hIL-2-specific mAb interacts with hIL-2 amino acid residues to provide an epitope, and

wherein the epitope comprises the hIL-2 residues

H16, D20,

Q57, E60, E61, L63, K64, E67, E68, and

L80, R81, R83, D84, 186, S87, N88, N90, V91, L94, E95, K97, T101, T102, M104;

wherein the hIL-2-specific mAb, or antigen-binding fragment thereof comprises a heavy chain variable (V H ) region comprising a V H complementarity determining region CDR H 1, CDR H 2 and CDR H 3, and a variable light chain (V L ) region comprising a V L complementarity determining region CDR L 1, CDR L 2 and CDR L 3, and wherein

a. CDR H 1 comprises, or is identical to SEQ ID NO 001; and

b. CDR H 2 comprises, or is identical to SEQ ID NO 002, and

c. CDR H 3, comprises, or is identical to SEQ ID NO 003; and

d. CDR L 1 comprises, or is identical to SEQ ID NO 004; and

e. CDR L 2 comprises, or is identical to SEQ ID NO 005; and

f. CDR L 3 comprises, or is identical to SEQ ID NO 006.

2 . A hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 , wherein the binding of the hIL-2-specific mAb to hIL-2 is characterized by:

a dissociation constant (K D ) equal or smaller than (≤) 5.51×10 −9 ,

an on-rate (K on ) equal or greater than (≥) 4.12×10 5 Ms −1 , and

an off-rate (K off )≤83×10−3 s −1 .

3 . The hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 , wherein a complex of the hIL-2-specific mAb and hIL-2 combined in a ratio between 2:1 to 1:2 is characterized by:

a ratio of binding to the high-affinity hIL-2 receptor compared to the intermediate-affinity hIL-2 receptor of between 20 to 121, and/or

a ratio of binding affinity for CD25 alone, compared to the intermediate-affinity hIL-2 receptor of between 277 to 483, and/or

dissociation of the hIL-2 mAb from hIL-2 on binding of the complex to the high-affinity hIL-2 receptor, and/or

activating human CD3 + CD4 + CD127 low Foxp3 + T reg cells with an EC50≤0.154, and human CD8 + T cells with an EC50≥442.9.

4 . A hIL-2-specific mAb, or antigen-binding fragment thereof, which comprises a heavy chain variable (V H ) region comprising a V H complementarity determining region CDR H 1, CDR H 2 and CDR H 3, and a variable light chain (V L ) region comprising a V L complementarity determining region CDR L 1, CDR L 2 and CDR L 3, and wherein

a. CDR H 1 comprises, or is identical to SEQ ID NO 001; and

b. CDR H 2 comprises, or is identical to SEQ ID NO 002, and

c. CDR H 3, comprises, or is identical to SEQ ID NO 003; and

d. CDR L 1 comprises, or is identical to SEQ ID NO 004; and

e. CDR L 2 comprises, or is identical to SEQ ID NO 005; and

f. CDR L 3 comprises, or is identical to SEQ ID NO 006.

5 . A hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 , wherein

a. the CDR H 1, CDR H 2 and CDR H 3 are comprised in a V H sequence selected from SEQ ID NO 007, SEQ ID NO 008, SEQ ID NO 009, SEQ ID NO 010, SEQ ID NO 011, SEQ ID NO 012, SEQ ID NO 013, and SEQ ID NO 014, and wherein,

b. the CDR L 1, CDR L 2 and CDR L 3 are comprised in a V L sequence selected from SEQ ID NO 015, and SEQ ID NO 016.

6 . The hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 , and further comprising

a. a first sequence ≥90% identical, to at least one of SEQ ID NO 007, SEQ ID NO 008, SEQ ID NO 009, SEQ ID NO 010, SEQ ID NO 011, SEQ ID NO 012, SEQ ID NO 013, SEQ ID NO 014, and SEQ ID NO 017; and

b. a second sequence ≥90% identical to at least one of SEQ ID NO 015, SEQ ID NO 016, and SEQ ID NO 018.

7 . The hIL-2-specific mAb according to claim 1 , wherein the hIL-2-specific mAb comprises:

a. a heavy chain, said heavy chain comprising or consisting of SEQ ID NO 017; and

b. a light chain, said light chain comprising or consisting of SEQ ID NO 018.

8 . A nucleic acid molecule encoding the hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 .

9 . A method of treatment for immune-mediated diseases comprising:

administrating to a patient in need an effective amount of a pharmaceutical composition

a. the hIL-2-specific mAb, or antigen-binding fragment thereof, according to claim 1 , and

b. hIL-2,

wherein the immune-mediated disease is selected from systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, autoimmune hepatitis, amyotrophic lateral sclerosis, type-1 diabetes mellitus, type-2 diabetes mellitus, atherosclerosis, multiple sclerosis, inflammatory and autoimmune myopathies, alopecia areata, psoriasis or inflammatory bowel disease

thereby treating the immune-mediated diseases.

10 . The method of claim 9 , wherein the IL-2 and the hIL-2-specific mAb are covalently associated.

11 . The method of claim 9 , wherein the allograft related disorder is diagnosed in a patient receiving a solid organ transplant procedure.