Modified TNF-α antibodies and uses thereof
The present disclosure relates to modified anti-TNFα polypeptides, compositions comprising modified anti-TNFα polypeptides, methods of making the same, and methods of using the modified anti-TNFα polypeptides for treatment of diseases. In one aspect, the disclosure relates to the treatment of inflammatory disorders using the modified anti-TNFα polypeptides.
1. A composition comprising:
an anti-tumor necrosis factor α (TNFα) antibody or antigen binding fragment;
a modified IL-2 polypeptide comprising amino acid substitutions Y31H, K35R, and Q74P, wherein residue position numbering is based on SEQ ID NO: 1 as a reference sequence; and
a linker, wherein the linker comprises:
a first point of attachment covalently attached to the modified IL-2 polypeptide; and
a second point of attachment covalently attached to the anti-TNFα antibody or antigen binding fragment.
2. The composition of claim 1 , wherein the modified IL-2 polypeptide exhibits an affinity for an IL-2 receptor α subunit which is at least about 100-fold greater than an IL-2 receptor β subunit.
3. The composition of claim 1 , wherein the modified IL-2 polypeptide further comprises an N88D amino acid substitution.
4. The composition of claim 1 , wherein the first point of attachment is at a N-terminal amino acid residue of the modified IL-2 polypeptide.
5. The composition of claim 1 , wherein the anti-TNFα antibody or antigen binding fragment is a full-length antibody.
6. The composition of claim 1 , wherein the anti-TNFα antibody or antigen binding fragment comprises an Fc region.
7. The composition of claim 6 , wherein the second point of attachment is at an amino acid residue in the Fc region.
8. The composition claim 6 , wherein the second point of position attachment is at the Fc region at a position of a K246 amino acid residue, a K248 amino acid residue, a K288 amino acid residue, a K317 amino acid residue, or a combination thereof (Eu numbering).
9. The composition of claim 8 , wherein the second point of attachment is at the K248 amino acid residue.
10. The composition of claim 1 , wherein the anti-TNFα antibody or antigen binding fragment is a monoclonal antibody.
11. The composition of claim 5 , wherein the full-length antibody comprises an IgG.
12. The composition of claim 11 , wherein the IgG is an IgG1, an IgG4, or is derived therefrom.
13. The composition of claim 1 , wherein the anti-TNFα antibody or antigen binding fragment comprises Adalimumab.
14. The composition of claim 1 , wherein the anti-TNFα antibody or antigen binding fragment comprises Infliximab.
15. The composition of claim 1 , wherein the second point of attachment is to a lysine residue of the anti-TNFα antibody or antigen binding fragment.
16. The composition of claim 1 , wherein the linker comprises a polymer.
17. The composition of claim 1 , wherein the linker comprises a structure:
wherein
is the first point of attachment to a lysine residue of the anti-TNFα antibody or antigen binding fragment;
L is a linking group; and
is a point of attachment to a linking group which connects to the first point of attachment.
18. The composition claim 1 , wherein the modified IL-2 polypeptide comprises an amino acid sequence of SEQ ID NO: 3.