JP-2022536898-A5 -

Dates

Publication Date

20230531

Application Date

20200612

Description

The above non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the subject matter of this disclosure. These examples should not be construed as limiting any of the embodiments described herein, including those relating to antibodies, pharmaceutical compositions or methods and their use for the treatment of cancer, neurodegenerative or infectious diseases. Furthermore, the present invention encompasses the following aspects. 1. A prodrug comprising an IL-15 cytokine moiety (A), a masking moiety (M), a carrier moiety (C), and a Sushi domain (S), wherein, The masking portion binds to the IL-15 cytokine portion, inhibiting the biological activity of the IL-15 cytokine portion. The masked area fuses with the NT area. The Sushi domain fuses with the carrier portion, and The IL-15 cytokine is fused to the Sushi domain. Prodrug. 2. The masking portion fuses with the carrier portion via the first peptide linker. The Sushi domain fuses to the carrier portion via the second peptide linker, and The IL-15 cytokine is fused to the Sushi domain via a third peptide linker, where at least one of the three peptide linkers is cleavable. The prodrug of item 1. 3. The prodrug of claim 2, wherein the third peptide linker has a length of at least 15, 20, 25, or 30 amino acids, and optionally, wherein the third peptide linker comprises SEQ ID NO: 139 or 140. 4. A prodrug comprising an IL-15 cytokine moiety (A), a masking moiety (M), a carrier moiety (C), and a Sushi domain (S), wherein, The masking portion binds to the IL-15 cytokine portion, inhibiting the biological activity of the IL-15 cytokine portion. The IL-15 cytokine portion fuses with the carrier portion, The Sushi domain fuses with the carrier portion, and The masked portion is fused into the Sushi domain. Prodrug. 5. The IL-15 cytokine portion fuses to the carrier portion via the first peptide linker. The Sushi domain fuses to the carrier portion via the second peptide linker, and The masking portion is fused to the Sushi domain via a third peptide linker, and optionally, at least one of the three peptide linkers is cleavable. Prodrug of item 4. 6. A prodrug from any of items 1 to 5, wherein the masking portion includes the extracellular domain (ECD) of the receptor for the IL-15 cytokine. 7. The prodrug of claim 6, wherein the masking portion comprises an ECD of human IL-2Rβ or a functional analog thereof and/or an ECD of human IL-2Rγ or a functional analog thereof. 8. The prodrug of claim 7, wherein the ECD of human IL-2Rγ or a functional analog thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 6. 9. A prodrug according to claim 7, wherein the ECD of human IL-2Rβ or a functional analog thereof comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3, 4, or 5. 10. Any prodrug from items 1 to 5, wherein the masking portion contains an antibody fragment that binds to the IL-15 cytokine portion. 11. A prodrug comprising an IL-15 cytokine moiety (A), a masking moiety (M), a carrier moiety (C), and optionally a Sushi domain (S), wherein, The masking portion binds to the IL-15 cytokine portion, and the antibody fragment contains a masking portion that inhibits the biological activity of the IL-15 cytokine portion, and The masking portion fuses to the carrier portion, the IL-15 cytokine portion, or the Sushi domain via a peptide linker. Prodrug. 12. A prodrug of item 10 or 11, which is an ScFv or Fab comprising heavy chain CDR1-3 and light chain CDR1-3 of an anti-IL-15 antibody, the antibody fragment selected from 146B7, 146H5, 404E4, and 404A8. 13. A prodrug of item 10 or 11, wherein the antibody fragment comprises heavy chain CDR (HCDR) 1 containing SEQ ID NO: 100, HCDR 2 containing SEQ ID NO: 101, HCDR 3 containing SEQ ID NO: 102 or 106, light chain CDR (LCDR) 1 containing SEQ ID NO: 103, LCDR 2 containing SEQ ID NO: 104, and LCDR 3 containing SEQ ID NO: 105. 14. A prodrug of item 10 or 11, wherein the antibody fragment comprises (i) a heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 107 or at least 95% identical thereto and a light chain variable domain comprising an amino acid sequence of SEQ ID NO: 108 or 123 or at least 95% identical thereto; (ii) SEQ ID NO: 109; (iii) SEQ ID NO: 110; or (iv) SEQ ID NO: 124. 15. A prodrug of item 13 or 14, wherein the Cys residue of the heavy chain CDR3 is mutated to Ser, Thr, Met, Ala, Gly, Asn, or Gln. 16. Any prodrug according to items 1 to 15, wherein the masking portion does not interfere with or has minimal effect on the binding of the IL-15 cytokine portion to IL-15Rα. 17. Any prodrug from items 1 to 16, wherein the IL-15 cytokine portion is a human IL-15 polypeptide or a mutant protein thereof containing SEQ ID NO: 2. 18. Human IL-15 polypeptides correspond to SEQ ID NO: N1A, N1D, N4A, N4D, I6T, S7A, D8A, D8T, D8E, D8N, K10A, K10D, K11A, K11D, E46, V49, L45, S51, L52, D61A, D61N, T62