JPWO2019204655A5 - - Google Patents

Claims (12)

Heterodimer fusion protein
a) The first monomer, from the N-terminal to the C-terminal,
i) IL-15Rα (sushi) domain,
ii) First domain linker,
iii) IL-15 variants of the amino acid sequence set forth in SEQ ID NO: 2, from N1D, N4D, D8N, D30N, D61N, E64Q, N65D, Q108E, N4D / N65D, D30N / N65D, and D30N / E64Q / N65D. IL-15 variant, which contains the amino acid substitutions (s) selected from the group :
iv) Hinge, and v) a first monomer comprising a first variant Fc domain comprising CH2-CH3, and
b) A second monomer, a second monomer that comprises VH-CH1-hinge-CH2-CH3 from the N-terminus to the C-terminus, wherein CH2-CH3 is the second variant Fc domain. With the body
c) Containing a third monomer containing VL-CL,
The VH and VL are variable heavy chain domains and variable light chain domains that form the human TIM-3 antigen binding domain, respectively.
The first variant Fc domain comprises skew variant L368D / K370S and the second variant Fc domain comprises skew variant S364K / E357Q.
The first and second variant Fc domains each include the FcKO variant E233P / L234V / L235A / G236del / S267K.
The first variant Fc domain comprises the pI variants Q295E / N384D / Q418E / N421D, numbered according to EU numbering, a heterodimer fusion protein. The heterodimer fusion protein of claim 1, wherein the hinge of the first monomer comprises an amino acid substitution C220S and is numbered according to EU numbering. The heterodimer fusion protein of claim 1 or 2, wherein the first and second variant Fc domains each further comprise an amino acid substitution M428 / N434S and are numbered according to EU numbering . The heterodimer fusion protein of claim 1 , wherein the IL-15 variant comprises amino acid substitutions N4D / N65D, D30N / N65D or D30N / E64Q / N65D. The VHs and VLs are SEQ ID NOs: 56 and 60, SEQ ID NOs: 64 and 68, SEQ ID NOs: 72 and 76, SEQ ID NOs: 80-84, SEQ ID NOs: 88 and 92, SEQ ID NOs: 96 and 100, SEQ ID NOs: 104 and 108, and SEQ ID NOs. 112 and 116, SEQ ID NOs: 120 and 124, SEQ ID NOs: 128 and 132, SEQ ID NOs: 136 and 140, SEQ ID NOs: 144 and 148, SEQ ID NOs: 152 and 156, SEQ ID NOs: 160 and 164, SEQ ID NOs: 168 and 172, SEQ ID NOs: 176 and The heterogeneous according to any one of claims 1 to 4 , which is a variable heavy chain domain and a variable domain of any of the TIM-3 antigen-binding domains selected from the group consisting of 180 and SEQ ID NOs: 184 and 188. Quantitative fusion protein. The heterodimer fusion protein of claim 5 , wherein the TIM-3 antigen binding domain is SEQ ID NOs: 72 and 76 . The heterodimeric fusion proteins are SEQ ID NOs: 241 and 242 and 243 , SEQ ID NOs: 246, 247 and 248 , SEQ ID NOs: 267, 268 and 269 , SEQ ID NOs: 270, 271 and 272 , SEQ ID NOs: 273, 274 and 275, and The heterodimer fusion protein according to claim 1, selected from the group consisting of SEQ ID NOs: 276, 277 and 278 . Nucleic acid composition
a) The first nucleic acid encoding the first monomer according to any one of claims 1 to 7 .
b) The second nucleic acid encoding the second monomer according to any one of claims 1 to 7 .
c) A nucleic acid composition comprising a third nucleic acid encoding the third monomer according to any one of claims 1 to 7 . An expression vector composition
a) The first expression vector containing the first nucleic acid according to claim 8 .
b) The second expression vector containing the second nucleic acid according to claim 8 .
c) An expression vector composition comprising a third expression vector comprising the third nucleic acid according to claim 8 . A host cell comprising the expression vector composition of claim 9 . A method for producing a heterodimer fusion protein, comprising culturing the host cell according to claim 10 and recovering the heterodimer fusion protein from a cell culture. A pharmaceutical composition for treating cancer in a patient in need of treatment, comprising the heterodimer fusion protein according to any one of claims 1-7 .