Tumor necrosis factor (TNF) receptor superfamily (TNFRSF) receptor-activating antibody fusion proteins with FCγR-independent agonistic activity (TNFRSF receptor-activating antibody fusion proteins with FCγR-independent agonistic activity; TRAAFFIAA)

A fusion protein, comprising, in an N- to C-terminal order:

• (i) an anti-TNFRSF receptor antibody or an antigen-binding portion thereof selected from the group consisting of an anti-TNFR2 antibody or antigen-binding portion thereof, an anti-CD40 antibody or antigen-binding portion thereof, and an anti-Fn14 antibody or antigen-binding portion thereof, and
• (ii) a domain which is capable of binding to a structure of the cell surface in an FcyR-independent manner;
• wherein the fusion protein is capable of an increased stimulation of the TNFRSF receptor as compared to a protein comprising the anti-TNFRSF receptor antibody or the antigen-binding portion thereof according to (i) but lacking the domain according to (ii);
• wherein (i) comprises:
• (a) an anti-TNFR2 antibody or an antigen-binding portion thereof comprising a heavy chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 60, a CDR2 amino acid sequence according to SEQ ID NO:
• 61, and a CDR3 amino acid sequence according to SEQ ID NO:
• 62, and comprising a light chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 63, a CDR2 amino acid sequence according to SEQ ID NO:
• 64, and a CDR3 amino acid sequence according to SEQ ID NO:
• 65;
• (b) an anti-CD40 antibody or an antigen-binding portion thereof comprising a heavy chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 37, a CDR2 amino acid sequence according to SEQ ID NO:
• 38, and the CDR3 amino acid sequence LDY, and comprising a light chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 39, a CDR2 amino acid sequence according to SEQ ID NO:
• 40, and a CDR3 amino acid sequence according to SEQ ID NO:
• 41;
• (c) an anti-Fn14 antibody or an antigen-binding portion thereof comprising a heavy chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 54, a CDR2 amino acid sequence according to SEQ ID NO:
• 55, and a CDR3 amino acid sequence according to SEQ ID NO:
• 56, and comprising a light chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 57, a CDR2 amino acid sequence according to SEQ ID NO:
• 58, and a CDR3 amino acid sequence according to SEQ ID NO:
• 59;
• or
• (d) an anti-Fn14 antibody or an antigen-binding portion thereof comprising a heavy chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 84, a CDR2 amino acid sequence according to SEQ ID NO:
• 85, and a CDR3 amino acid sequence according to SEQ ID NO:
• 86, and comprising a light chain comprising a CDR1 amino acid sequence according to SEQ ID NO:
• 87, a CDR2 amino acid sequence according to SEQ ID NO:
• 88, and a CDR3 amino acid sequence according to SEQ ID NO:
• 89;
• and
• wherein the domain of (ii) is an Avelumab scFv.