TNFR2 agonists with improved stability

A polypeptide, comprising a binding domain consisting of three peptide tumor necrosis factor (TNF) homology domains of TNF-ligand family member proteins (THD) that specifically bind to the extracellular part of TNF receptor 2 (TNFR2), wherein the C-terminus of the first and second THD, respectively, which is in each case defined by the C-terminal sequence

• (SEQ ID NO:
• 3)
• V-Y-F-G-I-I,
• is linked to the N-terminus of the second and third THD, respectively, which is in each case defined by the N-terminal sequence
• (SEQ ID NO:
• 4)
• P-V-A-H-V
• through a peptide Xa, which is in each case independently selected and has a length of 9 to 10 amino acids, wherein the peptide Xa consists of
• XC-XL-XN
• wherein
• XC is A-L;
• XL is absent or is selected from the group consisting of G, G-G, G-G-G, and G-G-G-G (SEQ ID NO:
• 16);
• XN is selected from the group consisting of P-S-D-K (SEQ ID NO:
• 6), T-P-S-D-K (SEQ ID NO:
• 7), R-T-P-S-D-K (SEQ ID NO:
• 8), and S-R-T-P-S-D-K (SEQ ID NO:
• 9), and
• wherein the THD comprises a contiguous amino acid sequence consisting of amino acids 88 to 231 of full length human TNF alpha of SEQ ID NO:
• 5, but comprising the mutations D143N and A145R of the ectodomain of human TNF alpha corresponding to D219N and A221R, respectively, relative to SEQ ID NO:
• 5.