JP-2022532994-A5 -

Dates

Publication Date

20230502

Application Date

20200424

Description

The diagrams in the drawings are for illustrative purposes only, not for limitation. In certain embodiments, for example, the following items are provided: (Item 1) A biparatopic fusion protein comprising (a) a first antigen-binding protein or fragment that binds to a tumor antigen, (b) a second antigen-binding protein or fragment that binds to the tumor antigen, and (c) a polypeptide antigen that is a target of a cell therapy drug, antibody, or antibody-drug conjugate. (Item 2) The biparatopic fusion protein described in item 1, wherein the tumor antigen is a tumor-specific antigen (TSA). (Item 3) The biparatopic fusion protein described in item 1, wherein the tumor antigen is a tumor-associated antigen (TAA). (Item 4) The biparatopic fusion protein according to any one of items 1 to 3, wherein the first antigen-binding protein or fragment is scFv. (Item 5) The biparatopic fusion protein according to any one of items 1 to 3, wherein the second antigen-binding protein or fragment is VHH. (Item 6) A biparatopic fusion protein according to any one of items 1 to 3, wherein the first antigen-binding protein or fragment and the second antigen-binding protein or fragment are VHH. (Item 7) A biparatopic fusion protein according to any one of items 1 to 3, wherein the first antigen-binding protein or fragment and the second antigen-binding protein or fragment are scFv, affibody, adonectin, or ankyrin repeat protein. (Item 8) A biparatopic fusion protein according to any one of items 1 to 7, wherein the tumor antigen is CLL-1. (Item 9) The biparatopic fusion protein according to any one of items 1 to 8, wherein the polypeptide antigen is a CD19 variant comprising at least one amino acid substitution in the amino acid sequence of SEQ ID NO: 2. (Item 10) A biparatopic fusion protein according to any one of items 1 to 9, wherein the CD19 variant comprises one or more amino acid substitutions of SEQ ID NO: 2 listed in Table 1A, Table 1B, Table 2A, Table 2B, Table 3, Table 6, Figure 3, Figure 4B, Figure 5A, Figure 5B, Figure 5C, Figure 5D, or Figure 6. (Item 11) The biparatopic fusion protein according to any one of items 5 to 10, wherein the VHH comprises one amino acid sequence or fragment thereof from sequence numbers 203 to 225. (Item 12) The biparatopic fusion protein according to item 11, wherein the VHH comprises a portion of any one of the amino acid sequences of SEQ ID NOs. 203 to 225 (e.g., a CLL-1 binding portion), and the portion lacks all of the C-terminal amino acids TSGPGGQGAEQKLISEEDLGAHHHHHHHGAS shown in each of SEQ ID NOs. 203 to 225. (Item 13) The biparatopic fusion protein described in any one of items 5 to 7, wherein the VHH comprises CDR1, CDR2, and CDR3 of group 1 as shown in Table 5A and/or Table 5B; CDR1, CDR2, and CDR3 of group 2; CDR1, CDR2, and CDR3 of group 3; CDR1, CDR2, and CDR3 of group 4; CDR1, CDR2, and CDR3 of group 5; CDR1, CDR2, and CDR3 of group 6; CDR1, CDR2, and CDR3 of group 7; CDR1, CDR2, and CDR3 of group 8; CDR1, CDR2, and CDR3 of group 9; CDR1, CDR2, and CDR3 of group 10; or CDR1, CDR2, and CDR3 of group 13. (Item 14) The biparatopic fusion protein according to any one of items 1 to 13, wherein the cell therapy is CAR-T cells, CAR-NK cells, TCR-T cells, TIL cells, allogeneic NK cells, or autologous NK cells. (Item 15) The biparatopic fusion protein described in item 14, wherein the aforementioned CAR-T or CAR-NK is an allogeneic. (Item 16) The biparatopic fusion protein described in item 14, wherein the CAR-T or CAR-NK is of self-derived origin. (Item 17) (i) an antigen-binding receptor comprising an antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain that binds to a first tumor antigen, (ii) A cell comprising a constitutive expression construct encoding a biparatopic fusion protein comprising (a) a first antigen-binding protein or fragment that binds to a second tumor antigen, (b) a second antigen-binding protein or fragment that binds to the second tumor antigen, and (c) a polypeptide antigen that is a target of a cell therapy drug, antibody, or antibody-drug conjugate. (Item 18) The cell described in item 17, wherein the first tumor antigen is CD19. (Item 19) The cell according to item 17 or 18, wherein the tumor antigen is a tumor-specific antigen (TSA) or a tumor-associated antigen (TAA). (Item 20) The cells described in item 17 or 18, wherein the tumor antigen is a tumor-associated antigen (TAA). (Item 21) The cell according to any one of items 17 to 20, wherein the first antigen-binding protein or fragment is scFv. (Item 22) The cell according to any one of items 17 to 20, wherein the second antigen-binding protein or fragment is VHH. (Item 23) A cell according to any one of items 17 to 20, wherein the first antigen-binding protein or fragment and the second antigen-binding protein or fragment are VHH. (Item 24) A cell according to any one of items 17 to 20, wherein the first antigen-binding protein or fragment and the second antigen-bindi