ANTITUMOR IMMUNE CHECKPOINT REGULATOR ANTAGONISTS
Antitumor antagonists that bind specifically to immune checkpoint regulator are disclosed. Also disclosed is a method of treating proliferative disorders with the antitumor antagonists.
1 . An antitumor antagonist comprising:
a first targeting domain that specifically binds to PD-1, PD-L1 or LAG-3; and
a second targeting domain comprising an scFv that specifically binds to TIGIT.
2 . The antitumor antagonist of claim 1 , wherein the scFv comprises:
an immunoglobulin heavy chain variable region (HCVR) having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48, 50, 52, 54, 56, 58, 60, 62, 64, and 66; and/or
immunoglobulin light chain variable region (LCVR) having at at least 90% identity comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 49, 51, 53, 55, 57, 59, 61, 63, 65, and 67, or both.
3 . The antitumor antagonist of claim 1 , wherein the scFv comprises:
an immunoglobulin HCVR having at least 90% identity to the amino acid sequence of SEQ ID NO: 66; and/or
an immunoglobulin LCVR comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 67.
4 . The antitumor antagonist of claim 3 , wherein the scFv comprises:
an immunoglobulin HCVR comprising the amino acid sequence of SEQ ID NO:66; and/or
an immunoglobulin LCVR comprising the amino acid sequence of SEQ ID NO:67.
5 . The antitumor antagonist of claim 1 , comprising an immunoglobulin scaffold having an amino terminus and a carboxy terminus.
6 . The antitumor antagonist of claim 5 , wherein the first targeting domain is linked to the amino terminus of the immunoglobulin scaffold and the second targeting domain is linked to the carboxy terminus of immunoglobulin scaffold via a peptide linker.
7 . The antitumor antagonist of claim 6 , wherein the peptide linker comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 188-191.
8 . The antitumor antagonist of claim 6 , wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:191.
9 . The antitumor antagonist of claim 1 , wherein the first targeting domain specifically binds to PD-1.
10 . The antitumor antagonist of claim 9 , wherein the first targeting domain comprises:
(1) an immunoglobulin HCVR comprising three complementarity determining regions (HCDRs): HCDR1, HCDR2 and HCDR3,
wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 68, 71, 74, 76 and 79,
wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 69, 72, 77 and 80, and
wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 70, 73, 75, 78 and 81; and
(2) an immunoglobulin LCVR comprising three complementarity determining regions (LCDRs): LCDR1, LCDR2 and LCDR3,
wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 82, 85, 88, 89, 90 and 93,
wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 83, 86, 91 and 94, and
wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 84, 87, 92 and 95.
11 . The antitumor antagonist of claim 9 , wherein the first targeting domain comprises:
an immunoglobulin HCVR having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 96, 98, 100, 102, 104, and 106; and/or
an immunoglobulin LCVR having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 97, 99, 101, 103, 105, and 107.
12 . The antitumor antagonist of claim 9 , wherein the first targeting domain comprises:
an immunoglobulin HCVR comprising the amino acid sequence of SEQ ID NO:106; and/or
an immunoglobulin LCVR comprising the amino acid sequence of SEQ ID NO:107.
13 . The antitumor antagonist of claim 9 , comprising:
an immunoglobulin heavy chain having the amino acid sequence of SEQ ID NO: 160 or SEQ ID NO: 162; and/or
an immunoglobulin light chain having the amino acid sequence of SEQ ID NO: 161.
14 . The antitumor antagonist of claim 1 , wherein the first targeting domain specifically binds to PD-L1.
15 . The antitumor antagonist of claim 14 , wherein the first targeting domain comprises:
(1) an immunoglobulin HCVR comprising three HCDRs: HCDR1, HCDR2 and HCDR3,
wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 108, 111, 117 and 120,
wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 109, 112, 114, 116, 118, 121 and 125, and
wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 110, 113, 115, 119 and 122; and
(2) an immunoglobulin LCVR comprising three LCDRs: LCDR1, LCDR2 and LCDR3,
wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 123, 126, 130, 133 and 136,
wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 126, 127, 131, 134 and 137, and
wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 125, 128, 129, 132, 135 and 138.
16 . The antitumor antagonist of claim 14 , wherein the first targeting domain comprises:
an immunoglobulin HCVR having at least 90% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 139, 141, 143, 145, 147, 149, 151 and 153; and/or
an immunoglobulin LCVR having at least 90% identify to an amino acid sequence selected from the group consisting of SEQ ID NOS: 140, 142, 144, 146, 148, 150, 152 and 154.
17 . The antitumor antagonist of claim 14 , wherein the first targeting domain comprises:
an immunoglobulin HCVR having the amino acid sequence of SEQ ID NO:153; and/or
an immunoglobulin LCVR having the amino acid sequence of SEQ ID NO:154.
18 . An antitumor antagonist of claim 14 , comprising:
an immunoglobulin heavy chain having an amino acid sequence selected from the group consisting of SEQ ID NO: 339-341; and/or
an immunoglobulin light chain having the amino acid sequence of SEQ ID NO: 338.
19 . The antitumor antagonist of claim 1 , wherein the first targeting domain specifically binds LAG-3.
20 . The antitumor antagonist of claim 19 , wherein the first targeting domain comprises:
(1) an immunoglobulin HCVR comprising three HCDRs: HCDR1, HCDR2 and HCDR3,
wherein the HCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 163, 166 and 169,
wherein the HCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 164, 167 and 170, and
wherein the HCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 165, 168 and 171; and
(2) an immunoglobulin LCVR comprising three LCDRs: LCDR1, LCDR2 and LCDR3,
wherein the LCDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 172, 175 and 177,
wherein the LCDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 173 and 178, and
wherein the LCDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 174, 176 and 179.