Antibodies
An isolated antibody or fragment thereof, which specifically binds to a gamma variable 4 (Vγ4) chain of a γδ T cell receptor (TCR) and not to a gamma variable 2 (Vγ2) chain of a γδ TCR is provided herein. Methods of treatment and other uses of said antibodies are also provided along with methods of producing said antibodies.
1 . An isolated anti-gamma variable 4 (anti-Vγ4) antibody or fragment thereof comprising:
(a) a heavy chain variable (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 79, a heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 56 and a heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; and
a light chain variable (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 102, a light chain complementarity determining region 2 (LCDR2) of EVT and a light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 33;
(b) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 86, a HCDR2 of SEQ ID NO: 63 and a HCDR3 of SEQ ID NO: 17; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 109, a LCDR2 of QDS and a LCDR3 of SEQ ID NO: 40;
(c) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 73, a HCDR2 of SEQ ID NO: 50 and a HCDR3 of SEQ ID NO: 4; and
a VL comprising a LCDR1 of SEQ ID NO: 96, a LCDR2 of DAS and a LCDR3 of SEQ ID NO: 27;
(d) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 83, a HCDR2 of SEQ ID NO: 60 and a HCDR3 of SEQ ID NO: 14; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 106, a LCDR2 of EIT and a LCDR3 of SEQ ID NO: 37;
(e) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 84, a HCDR2 of SEQ ID NO: 61 and a HCDR3 of SEQ ID NO: 15; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 107, a LCDR2 of RDS and a LCDR3 of SEQ ID NO: 38;
(f) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 88, a HCDR2 of SEQ ID NO: 65 and a HCDR3 of SEQ ID NO: 19; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 111, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 42;
(g) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 92, a HCDR2 of SEQ ID NO: 69 and a HCDR3 of SEQ ID NO: 23; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 115, a LCDR2 of GKN and a LCDR3 of SEQ ID NO: 46;
(h) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 71, a HCDR2 of SEQ ID NO: 48 and a HCDR3 of SEQ ID NO: 2; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 94, a LCDR2 of DAS and a LCDR3 of SEQ ID NO: 25;
(i) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 72, a HCDR2 of SEQ ID NO: 49 and a HCDR3 of SEQ ID NO: 3; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 95, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 26;
(j) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 74, a HCDR2 of SEQ ID NO: 51 and a HCDR3 of SEQ ID NO: 5; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 97, a LCDR2 of WAS and a LCDR3 of SEQ ID NO: 28;
(k) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 75, a HCDR2 of SEQ ID NO: 52 and a HCDR3 of SEQ ID NO: 6; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 98, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 29;
(l) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 76, a HCDR2 of SEQ ID NO: 53 and a HCDR3 of SEQ ID NO: 7; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 99, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 30;
(m) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 77, a HCDR2 of SEQ ID NO: 54 and a HCDR3 of SEQ ID NO: 8; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 100, a LCDR2 of LGS and a LCDR3 of SEQ ID NO: 31;
(n) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 78, a HCDR2 of SEQ ID NO: 55 and a HCDR3 of SEQ ID NO: 9; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 101, a LCDR2 of KVS and a LCDR3 of SEQ ID NO: 32;
(o) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 80, a HCDR2 of SEQ ID NO: 57 and a HCDR3 of SEQ ID NO: 11; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 103, a LCDR2 of EDN and a LCDR3 of SEQ ID NO: 34;
(p) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 81, a HCDR2 of SEQ ID NO: 58 and a HCDR3 of SEQ ID NO: 12; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 104, a LCDR2 of RDK and a LCDR3 of SEQ ID NO: 35;
(q) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 82, a HCDR2 of SEQ ID NO: 59 and a HCDR3 of SEQ ID NO: 13; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 105, a LCDR2 of DVS and a LCDR3 of SEQ ID NO: 36;
(r) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 85, a HCDR2 of SEQ ID NO: 62 and a HCDR3 of SEQ ID NO: 16; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 108, a LCDR2 of DDD and a LCDR3 of SEQ ID NO: 39;
(s) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 87, a HCDR2 of SEQ ID NO: 64 and a HCDR3 of SEQ ID NO: 18; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 110, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 41;
(t) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 89, a HCDR2 of SEQ ID NO: 66 and a HCDR3 of SEQ ID NO: 20; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 112, a LCDR2 of WAS and a LCDR3 of SEQ ID NO: 43;
(u) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 90, a HCDR2 of SEQ ID NO: 67 and a HCDR3 of SEQ ID NO: 21; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 113, a LCDR2 of EVS and a LCDR3 of SEQ ID NO: 44;
(v) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 91, a HCDR2 of SEQ ID NO: 68 and a HCDR3 of SEQ ID NO: 22; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 114, a LCDR2 of EVS and a LCDR3 of SEQ ID NO: 45;
or
(w) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 93, a HCDR2 of SEQ ID NO: 70 and a HCDR3 of SEQ ID NO: 24; and
a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 116, a LCDR2 of GKN and a LCDR3 of SEQ ID NO: 47.
2 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising an amino acid sequence of any one of SEQ ID NOs: 163-185.
3 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising an amino acid sequence of any one of SEQ ID NOs: 233-255.
4 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising a heavy chain amino acid sequence of any one of SEQ ID NOs: 284-306 and a light chain amino acid sequence of any one of SEQ ID NOs: 307-329.
5 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 , wherein the isolated anti-Vγ4 antibody or fragment thereof is:
(i) an scFv or a full length antibody; and/or
(ii) a human antibody or fragment thereof.
6 . A polynucleotide sequence encoding the anti-Vγ4 antibody or fragment thereof of claim 1 .
7 . An expression vector comprising the polynucleotide sequence of claim 6 .
8 . A cell comprising the polynucleotide sequence of claim 6 .
9 . A composition comprising the antibody or fragment thereof of claim 1 .
10 . A pharmaceutical composition comprising the antibody or fragment thereof of claim 1 and a pharmaceutically acceptable diluent or carrier.
11 . A kit comprising an anti-Vγ4 antibody or fragment thereof of claim 1 .
12 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising:
(a) a VH comprising an amino acid sequence of SEQ ID NO: 125; and
a VL comprising an amino acid sequence of SEQ ID NO: 148 or 269;
(b) a VH comprising an amino acid sequence of SEQ ID NO: 132; and
a VL comprising an amino acid sequence of SEQ ID NO: 155 or 276;
(c) a VH comprising an amino acid sequence of SEQ ID NO: 119; and
a VL comprising an amino acid sequence of SEQ ID NO: 142 or 263;
(d) a VH comprising an amino acid sequence of SEQ ID NO: 129; and
a VL comprising an amino acid sequence of SEQ ID NO: 152 or 273;
(e) a VH comprising an amino acid sequence of SEQ ID NO: 130; and
a VL comprising an amino acid sequence of SEQ ID NO: 153 or 274;
(f) a VH comprising an amino acid sequence of SEQ ID NO: 134; and
a VL comprising an amino acid sequence of SEQ ID NO: 157 or 278;
(g) a VH comprising an amino acid sequence of SEQ ID NO: 138; and
a VL comprising an amino acid sequence of SEQ ID NO: 161 or 282;
(h) a VH comprising an amino acid sequence of SEQ ID NO: 117; and
a VL comprising an amino acid sequence of SEQ ID NO: 140 or 261;
(i) a VH comprising an amino acid sequence of SEQ ID NO: 118; and
a VL comprising an amino acid sequence of SEQ ID NO: 141 or 262;
(j) a VH comprising an amino acid sequence of SEQ ID NO: 120; and
a VL comprising an amino acid sequence of SEQ ID NO: 143 or 264;
(k) a VH comprising an amino acid sequence of SEQ ID NO: 121; and
a VL comprising an amino acid sequence of SEQ ID NO: 144 or 265;
(l) a VH comprising an amino acid sequence of SEQ ID NO: 122; and
a VL comprising an amino acid sequence of SEQ ID NO: 145 or 266;
(m) a VH comprising an amino acid sequence of SEQ ID NO: 123; and
a VL comprising an amino acid sequence of SEQ ID NO: 146 or 267;
(n) a VH comprising an amino acid sequence of SEQ ID NO: 124; and
a VL comprising an amino acid sequence of SEQ ID NO: 147 or 268;
(o) a VH comprising an amino acid sequence of SEQ ID NO: 126; and
a VL comprising an amino acid sequence of SEQ ID NO: 149 or 270;
(p) a VH comprising an amino acid sequence of SEQ ID NO: 127; and
a VL comprising an amino acid sequence of SEQ ID NO: 150 or 271;
(q) a VH comprising an amino acid sequence of SEQ ID NO: 128; and
a VL comprising an amino acid sequence of SEQ ID NO: 151 or 272;
(r) a VH comprising an amino acid sequence of SEQ ID NO: 131; and
a VL comprising an amino acid sequence of SEQ ID NO: 154 or 275;
(s) a VH comprising an amino acid sequence of SEQ ID NO: 133; and
a VL comprising an amino acid sequence of SEQ ID NO: 156 or 277;
(t) a VH comprising an amino acid sequence of SEQ ID NO: 135; and
a VL comprising an amino acid sequence of SEQ ID NO: 158 or 279;
(u) a VH comprising an amino acid sequence of SEQ ID NO: 136; and
a VL comprising an amino acid sequence of SEQ ID NO: 159 or 280;
(v) a VH comprising an amino acid sequence of SEQ ID NO: 137; and
a VL comprising an amino acid sequence of SEQ ID NO: 160 or 281; or
(w) a VH comprising an amino acid sequence of SEQ ID NO: 139; and
a VL comprising an amino acid sequence of SEQ ID NO: 162 or 283.
13 . A method of expanding a Vγ4+ T cell, the method comprising contacting the Vγ4+ T cell with the isolated anti-Vγ4 antibody or fragment thereof of claim 1 .
14 . A method of detecting a Vγ4+ T cell, the method comprising contacting a sample comprising the Vγ4+ T cell with the isolated anti-Vγ4 antibody or fragment thereof of claim 1 .
15 . A method of treating a cancer, an infectious disease or an inflammatory disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of the isolated anti-Vγ4 antibody or fragment thereof of claim 1 to the subject.