Therapeutic antibodies and their uses

Abstract

The present invention relates to antibodies that specifically bind to B7-H4 (B7 Homology 4, encoded by gene VTCN1) and bispecific antibodies that specifically bind to both B7-H4 and CD3 (Cluster of Differentiation 3), and polynucleotides, pharmaceutical compositions and methods and uses thereof.

It is claimed: 
     
         1 . An isolated antibody that specifically binds to B7-H4, comprising
 (a) a heavy chain variable region (VH) complementarity determining region (CDR) one (CDR1), a VH CDR2 and a VH CDR3 of a VH having an amino acid sequence selected from the group consisting of SEQ ID NO: 23, SEQ ID NO:155, SEQ ID NO: 156, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO:161, SEQ ID NO:163, SEQ ID NO:165, SEQ ID NO:169, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, SEQ ID NO: 175 and SEQ ID NO: 176; and   (b) a light chain variable region (VL) complementarity determining region one (CDR1), a VL CDR2 and a VL CDR3 of a VL having an amino acid sequence selected from the group consisting of SEQ ID NO:27, SEQ ID NO: 139, SEQ ID NO:141, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169 and SEQ ID NO:170.   
     
     
         2 . The antibody of  claim 1 , wherein the antibody comprises a VH CDR1, VH CDR2, VH CDR3, VL CDR1, VLCDR2, and VL CDR3 from an antibody comprising
 (a) the VH having the amino acid sequence of SEQ ID NO:161; and the VL having the amino acid sequence of SEQ ID NO:167;   (b) the VH having the amino acid sequence of SEQ ID NO:172; and the VL having the amino acid sequence of SEQ ID NO:139;   (c) the VH having the amino acid sequence of SEQ ID NO:155; and the VL having the amino acid sequence of SEQ ID NO:139;   (d) the VH having the amino acid sequence of SEQ ID NO:156; and the VL having the amino acid sequence of SEQ ID NO:139;   (e) the VH having the amino acid sequence of SEQ ID NO:157; and the VL having the amino acid sequence of SEQ ID NO:141;   (f) the VH having the amino acid sequence of SEQ ID NO:155; and the VL having the amino acid sequence of SEQ ID NO:141;   (g) the VH having the amino acid sequence of SEQ ID NO:156; and the VL having the amino acid sequence of SEQ ID NO:141;   (h) the VH having the amino acid sequence of SEQ ID NO:159; and the VL having the amino acid sequence of SEQ ID NO:27;   (i) the VH having the amino acid sequence of SEQ ID NO:161; and the VL having the amino acid sequence of SEQ ID NO:27;   (j) the VH having the amino acid sequence of SEQ ID NO:163; and the VL having the amino acid sequence of SEQ ID NO:27;   (k) the VH having the amino acid sequence of SEQ ID NO:165; and the VL having the amino acid sequence of SEQ ID NO:27;   (l) the VH having the amino acid sequence of SEQ ID NO:23; and the VL having the amino acid sequence of SEQ ID NO:167;   (m) the VH having the amino acid sequence of SEQ ID NO:171; and the VL having the amino acid sequence of SEQ ID NO:141;   (n) the VH having the amino acid sequence of SEQ ID NO:172; and the VL having the amino acid sequence of SEQ ID NO:141;   (o) the VH having the amino acid sequence of SEQ ID NO:171; and the VL having the amino acid sequence of SEQ ID NO:139;   (p) the VH having the amino acid sequence of SEQ ID NO:173; and the VL having the amino acid sequence of SEQ ID NO:139;   (q) the VH having the amino acid sequence of SEQ ID NO:174; and the VL having the amino acid sequence of SEQ ID NO:139;   (r) the VH having the amino acid sequence of SEQ ID NO:175; and the VL having the amino acid sequence of SEQ ID NO:139;   (s) the VH having the amino acid sequence of SEQ ID NO:161; and the VL having the amino acid sequence of SEQ ID NO:168;   (t) the VH having the amino acid sequence of SEQ ID NO:161; and the VL having the amino acid sequence of SEQ ID NO:169;   (u) the VH having the amino acid sequence of SEQ ID NO:161; and the VL having the amino acid sequence of SEQ ID NO:170; or   (v) the VH having the amino acid sequence of SEQ ID NO:172; and the VL having the amino acid sequence of SEQ ID NO:139.   
     
     
         3 . The antibody of  claim 1 , comprising
 (a) a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (b) a VH CDR1 having the amino acid sequence of SEQ ID NO: 205; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (c) a VH CDR1 having the amino acid sequence of SEQ ID NO: 206; a VH CDR2 having the amino acid sequence of SEQ ID NO:207, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (d) a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (e) a VH CDR1 having the amino acid sequence of SEQ ID NO: 199; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (f) a VH CDR1 having the amino acid sequence of SEQ ID NO: 200; a VH CDR2 having the amino acid sequence of SEQ ID NO:201, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (g) a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, a VL CDR1 having the amino acid sequence of SEQ ID NO: 152, a VL CDR2 having the amino acid sequence of SEQ ID NO:41 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (h) a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138; or   (i) a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:130, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138.   
     
     
         4 . The antibody of  claim 1 , further comprising a constant region, and wherein the antibody is a human IgG2 comprising substitutions C223E, P228E and L368E, wherein the numbering is according to human IgG2 wildtype and the EU numbering scheme, and as shown in  FIG.  1   . 
     
     
         5 . The antibody of  claim 4 , wherein the antibody comprises the substitutions A330S, P331S and D265A. 
     
     
         6 . An isolated antibody that specifically binds to B7-H4, comprising a heavy chain comprising the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) of the polynucleotide deposited under ATCC Accession No. PTA-126779, and a light chain comprising the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) of the polynucleotide deposited under with ATCC Accession No. PTA-126781. 
     
     
         7 . The antibody of  claim 1 , wherein
 (a) each of the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 is defined in accordance with the Kabat definition;   (b) each of the VH CDR1, the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 is defined in accordance with the Chothia definition;   (c) VH CDR1 is defined according to the AbM definition, and each of the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 is defined according to the Kabat definition; or   (d) VH CDR1 is defined according to the AbM definition, and each of the VH CDR2, the VH CDR3, the VL CDR1, the VL CDR2 and the VL CDR3 is defined according to the Chothia definition.   
     
     
         8 . An isolated first antibody that specifically binds to B7-H4, that competes for binding with B7-H4 with a second antibody comprising
 (a) a VH having the amino acid sequence of SEQ ID NO:8, and a VL having the amino acid sequence of SEQ ID NO:13;   (b) a VH having the amino acid sequence of SEQ ID NO:8, and a VL having the amino acid sequence of SEQ ID NO:13;   (c) a VH having the amino acid sequence of SEQ ID NO:39, and a VL having the amino acid sequence of SEQ ID NO:43;   (d) a VH having the amino acid sequence of SEQ ID NO:46, and a VL having the amino acid sequence of SEQ ID NO:49;   (e) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:54;   (f) a VH having the amino acid sequence of SEQ ID NO:57, and a VL having the amino acid sequence of SEQ ID NO:60;   (g) a VH having the amino acid sequence of SEQ ID NO:16, and a VL having the amino acid sequence of SEQ ID NO:19;   (h) a VH having the amino acid sequence of SEQ ID NO:64, and a VL having the amino acid sequence of SEQ ID NO:67;   (i) a VH having the amino acid sequence of SEQ ID NO:69, and a VL having the amino acid sequence of SEQ ID NO:70;   (j) a VH having the amino acid sequence of SEQ ID NO:74, and a VL having the amino acid sequence of SEQ ID NO:77;   (k) a VH having the amino acid sequence of SEQ ID NO:80, and a VL having the amino acid sequence of SEQ ID NO:84;   (l) a VH having the amino acid sequence of SEQ ID NO:87, and a VL having the amino acid sequence of SEQ ID NO:90;   (m) a VH having the amino acid sequence of SEQ ID NO:23, and a VL having the amino acid sequence of SEQ ID NO:27;   (n) a VH having the amino acid sequence of SEQ ID NO:94, and a VL having the amino acid sequence of SEQ ID NO:96;   (o) a VH having the amino acid sequence of SEQ ID NO:100, and a VL having the amino acid sequence of SEQ ID NO:77; or   (p) a VH having the amino acid sequence of SEQ ID NO:104, and a VL having the amino acid sequence of SEQ ID NO:67;   wherein the first antibody has a K D  to human B7-H4 of between about 1 micromolar and 0.1 nanomolar.   
     
     
         9 . An isolated antibody that specifically binds to B7-H4, wherein the antibody binds to an epitope on human B7-H4 comprising at least two amino acid residues selected from the group consisting of L44, K45, E46, G47, V48, L49, G50, L51, E64, D66, M68, T99 and K101 of the B7-H4 extracellular domain having the amino acid sequence of SEQ ID NO: 1. 
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antigen binding fragment of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . An isolated polynucleotide encoding: (i) a heavy chain of the antibody of any one of  claims 1  to  16 ; or (ii) a light chain of the antibody of  claim 1 . 
     
     
         12 . A vector comprising the polynucleotide of  claim 11 . 
     
     
         13 . An isolated host cell that recombinantly produces the antibody of  claim 1 . 
     
     
         14 . A method of treating a condition associated with cells expressing B7-H4 in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of  claim 10 . 
     
     
         15 . A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second arm which comprises a second antigen binding domain that binds to CD3, wherein
 (a) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (b) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 205; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (c) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 206; a VH CDR2 having the amino acid sequence of SEQ ID NO:207, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (d) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (e) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 200; a VH CDR2 having the amino acid sequence of SEQ ID NO:201, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (f) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 199; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138;   (g) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 152, a VL CDR2 having the amino acid sequence of SEQ ID NO:41 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153;   (h) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, and the first light chain comprises a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138; or   (i) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:130, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138.   
     
     
         16 . The bispecific antibody of  claim 15 , wherein
 (a) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167;   (b) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (c) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:155; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (d) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:156; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (e) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:157; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;   (f) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:155; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;   (g) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:156; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;   (h) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:159; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;   (i) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;   (j) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:163; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;   (k) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:165; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:27;   (l) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:23; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167;   (m) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:171; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;   (n) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:141;   (o) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:171; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (p) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:173; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (q) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:174; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (r) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:175; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139;   (s) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and a VL having the amino acid sequence of SEQ ID NO:168;   (t) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:169;   (u) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:170; or   (v) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172; and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139.   
     
     
         17 . The bispecific antibody of  claim 15 , wherein
 (a) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;   (b) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 202, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;   (c) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 203, a VH CDR2 having the amino acid sequence of SEQ ID NO:204, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34;   (d) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:116;   (e) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:109, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 111, a VL CDR2 having the amino acid sequence of SEQ ID NO:112 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34; or   (f) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:29, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 32, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34.   
     
     
         18 . The bispecific antibody of  claim 15 , wherein
 (a) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 108;   (b) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 115, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 117;   (c) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 110, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 113; or   (d) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 31, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO: 35.   
     
     
         19 . The bispecific antibody of  claim 15 , wherein
 (a) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 20; a VH CDR2 having the amino acid sequence of SEQ ID NO:21, a VH CDR3 having the amino acid sequence of SEQ ID NO:160, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 166, a VL CDR2 having the amino acid sequence of SEQ ID NO:25 and a VL CDR3 having the amino acid sequence of SEQ ID NO:153; and   (b) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34.   
     
     
         20 . The bispecific antibody of  claim 15 , wherein
 (a) the first heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 5; a VH CDR2 having the amino acid sequence of SEQ ID NO:6, a VH CDR3 having the amino acid sequence of SEQ ID NO:7, and the first light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, a VL CDR2 having the amino acid sequence of SEQ ID NO:10 and a VL CDR3 having the amino acid sequence of SEQ ID NO:138; and   (b) the second heavy chain comprises a VH CDR1 having the amino acid sequence of SEQ ID NO: 28, a VH CDR2 having the amino acid sequence of SEQ ID NO:105, a VH CDR3 having the amino acid sequence of SEQ ID NO:30, and the second light chain comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 107, a VL CDR2 having the amino acid sequence of SEQ ID NO:33 and a VL CDR3 having the amino acid sequence of SEQ ID NO:34.   
     
     
         21 . The bispecific antibody of  claim 15 , wherein
 (a) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:161, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:167; and   (b) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO:108.   
     
     
         22 . The bispecific antibody of  claim 15 , wherein
 (c) the first heavy chain comprises a VH having the amino acid sequence of SEQ ID NO:172, and the first light chain comprises a VL having the amino acid sequence of SEQ ID NO:139; and   (d) the second heavy chain comprises a VH having the amino acid sequence of SEQ ID NO: 106, and the second light chain comprises a VL having the amino acid sequence of SEQ ID NO:108.   
     
     
         23 . The bispecific antibody of  claim 15 , wherein the first arm further comprises human IgG2AA constant region with substitutions D265A, C223E, P228E, and L368E, the second arm further comprises a human IgG2AA constant region with substitutions D265A, C223R, E225R, P228R, and K409R, wherein the numbering is according to the human wildtype IgG2 and EU numbering schemes, and as shown in  FIG.  1   . 
     
     
         24 . A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second antigen binding domain that binds to CD3, wherein
 (a) the first heavy chain having the amino acid sequence of SEQ ID NO: 190; and the first light chain having the amino acid sequence of SEQ ID NO: 191; and   (b) the second heavy chain having the amino acid sequence of SEQ ID NO:188, and the second light chain having the amino acid sequence of SEQ ID NO: 189.   
     
     
         25 . A bispecific antibody that specifically binds to both B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain forms a second antigen binding domain that binds to CD3, wherein
 (a) the first heavy chain having the amino acid sequence of SEQ ID NO: 186; and the first light chain having the amino acid sequence of SEQ ID NO: 187; and   (b) the second heavy chain having the amino acid sequence of SEQ ID NO:188, and the second light chain having the amino acid sequence of SEQ ID NO:189.   
     
     
         26 . A bispecific antibody that specifically binds to B7-H4 and CD3, comprising a first heavy chain and a first light chain, and a second heavy chain and a second light chain, wherein the first heavy chain and the first light chain form a first antibody arm which comprises a first antigen binding domain that binds to B7-H4, and the second heavy chain and the second light chain form a second antigen binding domain that binds to CD3, wherein
 (a) the first heavy chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126779, and the first light chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126781; and   (b) the second heavy chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126780, and the second light chain comprises the amino acid sequence of the full-length polypeptide encoded by the open reading frame (ORF) deposited under ATCC Accession No. PTA-126782.   
     
     
         27 . A bispecific antibody that specifically binds to both B7-H4 and CD3, wherein the antibody binds to an epitope on human B7-H4 comprising at least two amino acid residue from the group consisting of L44, K45, E46, G47, V48, L49, G50, L51, S63, E64, D66, M68, T99 and K101 of the B7-H4 amino acid sequence of SEQ ID NO: 1. 
     
     
         28 . An isolated polynucleotide molecule encoding (i) a heavy chain of the antibody of  claim 15  (i) a light chain of the antibody of any one of  claim 15 . 
     
     
         29 . A vector comprising the polynucleotide molecule of  claim 28 . 
     
     
         30 . A host cell comprising the the vector of  claim 29 . 
     
     
         31 . A method of treating cancer in a subject in need comprising administering to the subject the bispecific antibody  claim 15 . 
     
     
         32 . A pharmaceutical composition comprising the bispecific antibody of  claim 15 . 
     
     
         33 . A method of treating a condition associated with malignant cells expressing B7-H4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 32 . 
     
     
         34 . The method of claim  43 , wherein the condition is a cancer. 
     
     
         35 . A method of inhibiting tumor growth or progression in a subject who has malignant cells expressing B7-H4, comprising administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 32 . 
     
     
         36 . A method of inducing tumor regression in a subject who has malignant cells expressing B7-H4, comprising administering to the subject in need thereof an effective amount of the pharmaceutical composition of  claim 32 .