ANTIGEN BINDING POLYPEPTIDES, ANTIGEN BINDING POLYPEPTIDE COMPLEXES AND METHODS OF USE THEREOF

1 - 107 . (canceled)

108 . An antigen binding polypeptide complex comprising a first polypeptide and a second polypeptide;

wherein the first polypeptide has a structure represented by:

VL1-VL2-VH2-VH1-Fc;

VH1-VH2-VL2-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-Fc;

VH1-L1-VH2-L2-VL2-L3-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or

VH1-L1-VH2-L2-VL2-L3-VL1-L4-Fc;

wherein the second polypeptide has a structure represented by:

VL3-VH3-Fc;

VH3-VL3-Fc;

VL3-L5-VH3-Fc; or

VH3-L5-VL3-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;

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;

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, L2, L3, L4 and L5 are amino acid linkers.

109 . The antigen binding polypeptide complex of claim 108 ,

wherein the first polypeptide has a structure represented by:

VL1-VL2-VH2-VH1-CH1-Fc;

VH1-VH2-VL2-VL1-CH1-Fc;

VL1-VL2-VH2-VH1-CL-Fc;

VH1-VH2-VL2-VL1-CL-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-L4-CH1-Fc;

VH1-L1-VH2-L2-VL2-L3-VL1-L4-CH1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-L4-CL-Fc; or

VH1-L1-VH2-L2-VL2-L3-VL1-L4-CL-Fc;

wherein the second polypeptide has a structure represented by:

VL3-VH3-CH1-Fc;

VH3-VL3-CH1-Fc;

VL3-VH3-CL-Fc;

VH3-VL3-CL-Fc;

VL3-L5-VH3-L6-CH1-L7-Fc;

VH3-L5-VL3-L6-CH1-L7-Fc;

VL3-L5-VH3-L6-CL-L7-Fc; or

VH3-L5-VL3-L6-CL-L7-Fc; and

wherein:

CH1 is an immunoglobulin heavy chain constant region 1;

CL is an immunoglobulin light chain constant region; and

L1, L2, L3, L4, L5, L6, and L7 are amino acid linkers.

110 . The antigen binding polypeptide complex of claim 108 ,

wherein the second polypeptide has a structure represented by:

VL3-VH3-CH1-CL-Fc;

VH3-VL3-CH1-CL-Fc;

VL3-VH3-CL-CH1-Fc;

VH3-VL3-CL-CH1-Fc;

VL3-L6-VH3-L7-CH1-L8-CL-Fc;

VH3-L6-VL3-L7-CH1-L8-CL-Fc;

VL3-L6-VH3-L7-CL-L8-CH1-Fc;

VH3-L6-VL3-L7-CL-L8-CH1-Fc;

VL3-VH3-L6-CH1-CL-Fc;

VH3-VL3-L6-CH1-CL-Fc;

VL3-VH3-L6-CL-CH1-Fc; or

VH3-VL3-L6-CL-CH1-Fc; and

wherein:

CH1 is an immunoglobulin heavy chain constant region 1;

CL is an immunoglobulin light chain constant region; and

L1, L2, L3, L4, L5, L6, L7 and L8 are amino acid linkers.

111 . The antigen binding polypeptide complex of claim 108 ,

wherein the second polypeptide has a structure represented by:

VL3-CL-VH3-CH1-Fc;

VL3-CH1-VH3-CL-Fc;

VH3-CH1-VL3-CL-Fc;

VH3-CL-VL3-CH1-Fc;

VL3-L6-CL-L7-VH3-L8-CH1-Fc;

VL3-L6-CH1-L7-VH3-L8-CL-Fc;

VH3-L6-CH1-L7-VL3-L8-CL-Fc;

VH3-L6-CL-L7-VL3-L8-CH1-Fc;

VL3-CL-L6-VH3-CH1-Fc;

VL3-CH1-L6-VH3-CL-Fc;

VH3-CH1-L6-VL3-CL-Fc; or

VH3-CL-L6-VL3-CH1-Fc; and

wherein:

CH1 is an immunoglobulin heavy chain constant region 1;

CL is an immunoglobulin light chain constant region; and

L1, L2, L3, L4, L5, L6, L7 and L8 are amino acid linkers.

112 . An antigen binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide;

wherein the first polypeptide has a structure represented by:

VL1-VL2-VH2-VH1-Fc;

VH1-VH2-VL2-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-Fc;

VH1-L1-VH2-L2-VL2-L3-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or

VH1-L1-VH2-L2-VL2-L3-VL1-L4-Fc;

wherein the second polypeptide has a structure represented by:

VL3; or

VL3-L5;

wherein the third polypeptide has a structure represented by:

VH3-Fc; or

VH3-L6-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;

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;

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, L2, L3, L4, L5 and L6 are amino acid linkers.

113 . The antigen binding polypeptide complex of claim 112 ,

wherein the second polypeptide has a structure represented by:

VL3-CH1;

VL3-CL;

VL3-L5-CH1; or

VL3-L5-CL;

wherein the third polypeptide has a structure represented by:

VH3-CH1-Fc;

VH3-CL-Fc;

VH3-L6-Fc;

VH3-L6-CH1-Fc; or

VH3-L6-CL-Fc; and

wherein:

CH1 is an immunoglobulin heavy chain constant region 1; and

CL is an immunoglobulin light chain constant region.

114 . An antigen binding polypeptide complex comprising a first polypeptide, a second polypeptide, and a third polypeptide;

wherein the first polypeptide has a structure represented by:

VL1-VL2-VH2-VH1-Fc;

VH1-VH2-VL2-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-Fc;

VH1-L1-VH2-L2-VL2-L3-VL1-Fc;

VL1-L1-VL2-L2-VH2-L3-VH1-L4-Fc; or

VH1-L1-VH2-L2-VL2-L3-VL1-L4-Fc;

wherein the second polypeptide has a structure represented by:

VL3-Fc; or

VL3-L5-Fc;

wherein the third polypeptide has a structure represented by:

VH3; or

VH3-L6; 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;

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;

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, L2, L3, L4, L5 and L6 are amino acid linkers.

115 . The antigen binding polypeptide complex of claim 114 ,

wherein the second polypeptide has a structure represented by:

VL3-CH1-Fc;

VL3-CL-Fc;

VL3-L5-CH1-Fc; or

VL3-L5-CL-Fc;

wherein the third polypeptide has a structure represented by:

VH3-CH1;

VH3-CL;

VH3-L6-CH1; or

VH3-L6-CL; and

wherein:

CH1 is an immunoglobulin heavy chain constant region 1; and

CL is an immunoglobulin light chain constant region.

116 . The antigen binding polypeptide complex of claim 108 , wherein VH1, VH2 and VH3 each bind to different antigens, and VL1, VL2 and VL3 each bind to different antigens.

117 . The antigen binding polypeptide complex of claim 108 , wherein linkers L1, L2, L3, L4 and L5 each comprise an amino acid sequence having at least 95% identity to any one of SEQ ID NOs:1-19 and 665-672.

118 . The antigen binding polypeptide complex of claim 112 , wherein linkers L1, L2, L3, L4, L5 and L6 each comprise an amino acid sequence having at least 95% identity to any one of SEQ ID NOs:1-19 and 665-672.

119 . The antigen binding polypeptide complex of claim 114 , wherein linkers L1, L2, L3, L4, L5 and L6 each comprise an amino acid sequence having at least 95% identity to any one of SEQ ID NOs:1-19 and 665-672.

120 . The antigen binding polypeptide complex of claim 108 , wherein the Fc region comprises at least one knob-into-hole modification.

121 . The antigen binding polypeptide complex of claim 112 , wherein the Fc region comprises at least one knob-into-hole modification.

122 . The antigen binding polypeptide complex of claim 114 , wherein the Fc region comprises at least one knob-into-hole modification.

123 . An antibody or antigen binding fragment thereof comprising the antigen binding polypeptide complex of claim 108 .

124 . The antibody or antigen binding fragment thereof of claim 123 , wherein the antigen binding fragment is a Fab, scFab, Fab′, F(ab′) 2 , Fv, or scFv.

125 . A polypeptide having at least 95% identity to any one of SEQ ID NOs:78-92.

126 . A polynucleotide having at least 95% identity to any one of SEQ ID NOs:93-107.

127 . A pharmaceutical composition comprising the antigen binding polypeptide complex of claim 108 , and (ii) a pharmaceutically acceptable carrier.

128 . A pharmaceutical composition comprising (i) a polynucleotide encoding the antigen binding polypeptide complex of claim 108 , and (ii) a pharmaceutically acceptable carrier.

129 . A method of treating or preventing a cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the antigen binding polypeptide complex of claim 108 .

130 . A method of treating or preventing a virus infection, comprising administering to a subject in need thereof a therapeutically effective amount of the antigen binding polypeptide complex of claim 108 .