IL-15 prodrugs and methods of use thereof

A prodrug comprising an IL-15 cytokine moiety (A), a masking moiety (M), a carrier moiety (C), and an IL-15Ra Sushi domain (S), wherein

• the masking moiety comprises an anti-IL-15 antibody fragment comprising a heavy chain CDR (HCDR) 1 comprising SEQ ID NO:
• 100, an HCDR2 comprising SEQ ID NO:
• 101, an HCDR3 comprising SEQ ID NO:
• 102 or 106, a light chain CDR (LCDR) 1 comprising SEQ ID NO:
• 103, an LCDR2 comprising SEQ ID NO:
• 104, and an LCDR3 comprising SEQ ID NO:
• 105,
• the masking moiety and the Sushi domain are each fused to the carrier moiety,
• the carrier moiety comprises an Fc domain derived from human IgG1 or IgG4, and
• the IL-15 cytokine moiety is fused to the Sushi domain, wherein the IL-15 cytokine moiety comprises a mutation at a position that corresponds to residue N65 of SEQ ID NO:
• 2 and wherein the IL-15 cytokine moiety has reduced affinity for IL-2Rβ compared to wildtype IL-15.