ANTIGEN BINDING POLYPEPTIDES, ANTIGEN BINDING POLYPEPTIDE COMPLEXES AND METHODS OF USE THEREOF
Disclosed are antigen binding polypeptides and antigen binding polypeptide complexes (e.g., antibodies and antigen binding fragments thereof) having certain structural features. Also disclosed are polynucleotides and vectors encoding such polypeptides and polypeptide complexes; host cells; chimeric antigen receptors (CARs); immune cells; pharmaceutical compositions and kits containing such polypeptides and polypeptide complexes; and methods of using such polypeptides and polypeptide complexes.
1 - 74 . (canceled)
75 . An antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide,
wherein the first polypeptide has a structure represented by:
VL1-L1-VL2-L2-VL3-L3-VH3-L4-VH2-L5-VH1-Fc;
VH1-L1-VH2-L2-VH3-L3-VL3-L4-VL2-L5-VL1-Fc;
VL1-L1-VH2-L2-VL3-L3-VH3-L4-VL2-L5-VH1-Fc;
VH1-L1-VL2-L2-VH3-L3-VL3-L4-VH2-L5-VL1-Fc;
VL1-L1-VL2-L2-VH3-L3-VL3-L4-VH2-L5-VH1-Fc;
VH1-L1-VH2-L2-VL3-L3-VH3-L4-VL2-L5-VL1-Fc;
VL1-L1-VH2-L2-VH3-L3-VL3-L4-VL2-L5-VH1-Fc;
VH1-L1-VL2-L2-VL3-L3-VH3-L4-VH2-L5-VL1-Fc;
VL1-L1-VL2-L2-VL3-L3-VH3-L4-VH2-L5-VH1-L6-Fc;
VH1-L1-VH2-L2-VH3-L3-VL3-L4-VL2-L5-VL1-L6-Fc;
VL1-L1-VH2-L2-VL3-L3-VH3-L4-VL2-L5-VH1-L6-Fc;
VH1-L1-VL2-L2-VH3-L3-VL3-L4-VH2-L5-VL1-L6-Fc;
VL1-L1-VL2-L2-VH3-L3-VL3-L4-VH2-L5-VH1-L6-Fc;
VH1-L1-VH2-L2-VL3-L3-VH3-L4-VL2-L5-VL1-L6-Fc;
VL1-L1-VH2-L2-VH3-L3-VL3-L4-VL2-L5-VH1-L6-Fc;
or
VH1-L1-VL2-L2-VL3-L3-VH3-L4-VH2-L5-VL1-L6-Fc;
wherein the second polypeptide has a structure represented by:
VL4-L7-VH4-Fc;
VH4-L7-VL4-Fc;
VL4-L7-VH4-L8-Fc;
VH4-L7-VL4-L8-Fc;
VL4-L7-VL5-L8-VH5-L9-VH4-Fc;
VH4-L7-VH5-L8-VL5-L9-VL4-Fc;
VL4-L7-VL5-L8-VH5-L9-VH4-L10-Fc;
VH4-L7-VH5-L8-VL5-L9-VL4-L10-Fc;
VL4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VH4-Fc;
VH4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VL4-Fc;
VL4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VH4-Fc;
VH4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VL4-Fc;
VL4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VH4-Fc;
VH4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VL4-Fc;
VL4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VH4-Fc;
VH4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VL4-Fc;
VL4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VH4-L12-Fc;
VH4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VL4-L12-Fc;
VL4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VH4-L12-Fc;
VH4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VL4-L12-Fc;
VL4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VH4-L12-Fc;
VH4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VL4-L12-Fc;
VL4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VH4-L12-Fc;
or
VH4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VL4-L12-Fc;
and
wherein:
VL1 is a first immunoglobulin light chain variable region;
VL2 is a second immunoglobulin light chain variable region;
VL3 is a third immunoglobulin light chain variable region;
VL4 is a fourth immunoglobulin light chain variable region;
VL5 is a fifth immunoglobulin light chain variable region;
VL6 is a sixth immunoglobulin light chain variable region;
VH1 is a first immunoglobulin heavy chain variable region;
VH2 is a second immunoglobulin heavy chain variable region;
VH3 is a third immunoglobulin heavy chain variable region;
VH4 is a fourth immunoglobulin heavy chain variable region;
VH5 is a fifth immunoglobulin heavy chain variable region;
VH6 is a sixth immunoglobulin heavy chain variable region;
Fc is a region comprising an immunoglobulin heavy chain constant region 2 (CH2), an immunoglobulin heavy chain constant region 3 (CH3), and optionally, an immunoglobulin hinge; and
L1-L12 are amino acid linkers.
76 . The antigen binding polypeptide complex of claim 75 , wherein the second polypeptide has a structure represented by:
VL4-L7-VH4-Fc;
VH4-L7-VL4-Fc;
VL4-L7-VH4-L8-Fc;
or
VH4-L7-VL4-L8-Fc.
77 . The antigen binding polypeptide complex of claim 75 , wherein the second polypeptide has a structure represented by:
VL4-L7-VL5-L8-VH5-L9-VH4-Fc;
VH4-L7-VH5-L8-VL5-L9-VL4-Fc;
VL4-L7-VL5-L8-VH5-L9-VH4-L10-Fc;
or
VH4-L7-VH5-L8-VL5-L9-VL4-L10-Fc.
78 . The antigen binding polypeptide complex of claim 75 , wherein the second polypeptide has a structure represented by:
VL4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VH4-Fc;
VH4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VL4-Fc;
VL4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VH4-Fc;
VH4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VL4-Fc;
VL4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VH4-Fc;
VH4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VL4-Fc;
VL4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VH4-Fc;
VH4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VL4-Fc;
VL4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VH4-L12-Fc;
VH4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VL4-L12-Fc;
VL4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VH4-L12-Fc;
VH4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VL4-L12-Fc;
VL4-L7-VL5-L8-VH6-L9-VL6-L10-VH5-L11-VH4-L12-Fc;
VH4-L7-VH5-L8-VL6-L9-VH6-L10-VL5-L11-VL4-L12-Fc;
VL4-L7-VH5-L8-VH6-L9-VL6-L10-VL5-L11-VH4-L12-Fc;
or
VH4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VL4-L12-Fc.
79 . The antigen binding polypeptide complex of claim 75 , wherein the first polypeptide has a structure represented by: VL1-L1-VL2-L2-VL3-L3-VH3-L4-VH2-L5-VH1-L6-Fc.
80 . The antigen binding polypeptide complex of claim 79 , wherein the second polypeptide has a structure represented by: VL4-L7-VH4-L8-Fc.
81 . The antigen binding polypeptide complex of claim 79 , wherein the second polypeptide has a structure represented by: VL4-L7-VL5-L8-VH5-L9-VH4-L10-Fc.
82 . The antigen binding polypeptide complex of claim 79 , wherein the second polypeptide has a structure represented by: VL4-L7-VL5-L8-VL6-L9-VH6-L10-VH5-L11-VH4-L12-Fc.
83 . The antigen binding polypeptide complex of claim 76 , wherein VL1 and VH1 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL2 and VH2 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL3 and VH3 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; and VL4 and VH4 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38.
84 . The antigen binding polypeptide complex of claim 77 , wherein VL1 and VH1 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL2 and VH2 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL3 and VH3 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL4 and VH4 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; and VL5 and VH5 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38.
85 . The antigen binding polypeptide complex of claim 78 , wherein VL1 and VH1 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL2 and VH2 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL3 and VH3 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL4 and VH4 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; VL5 and VH5 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38; and VL6 and VH6 specifically bind to BCMA, CD3, CD19, CD20, CD28, CD33 or CD38.
86 . The antigen binding polypeptide complex of claim 76 , wherein VL1 and VH1, VL2 and VH2, VL3 and VH3, and VL4 and VH4 specifically bind to different antigens.
87 . The antigen binding polypeptide complex of claim 77 , wherein VL1 and VH1, VL2 and VH2, VL3 and VH3, VL4 and VH4, and VL5 and VH5 specifically bind to different antigens.
88 . The antigen binding polypeptide complex of claim 78 , wherein VL1 and VH1, VL2 and VH2, VL3 and VH3, VL4 and VH4, VL5 and VH5, and VL6 and VH6 specifically bind to different antigens.
89 . The antigen binding polypeptide complex of claim 75 , wherein the Fc region comprises a knob-into-hole modification.
90 . An antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex of claim 75 .
91 . The antibody or antigen binding fragment thereof of claim 90 , wherein the antigen binding fragment is a Fab, scFab, Fab′, F(ab′) 2 , Fv, or scFv.
92 . A pharmaceutical composition comprising (i) the antigen binding polypeptide complex of claim 75 , and (ii) a pharmaceutically acceptable carrier.
93 . A chimeric antigen receptor (CAR) comprising the antigen binding polypeptide complex of claim 75 .
94 . An immune cell comprising the CAR of claim 93 .