Anti-TCR delta variable 1 antibodies

1 . An anti-TCR delta variable 1 (anti-Vδ1) antibody or antigen-binding fragment thereof comprising:

a) a variable heavy chain complementarity determining region 1 (VHCDR1), a variable heavy chain complementarity determining region 2 (VHCDR2) and a variable heavy chain complementarity determining region 3 (VHCDR3) comprising the amino acid sequences of SEQ ID NO: 51, 53 and 55, respectively, and a variable light chain complementarity determining region 1 (VLCDR1), a variable light chain complementarity determining region 2 (VLCDR2) and a variable light chain complementarity determining region 3 (VLCDR3) comprising the amino acid sequences of SEQ ID NO: 79, 80 and 82, respectively;

b) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 56, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 83, respectively;

c) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 57, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 84, respectively;

d) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 58, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 85, respectively;

e) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 59, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 86, respectively;

f) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 60, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 87, respectively;

g) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 52, 53 and 61, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 88, respectively;

h) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 62, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 89, respectively;

i) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 63, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 90, respectively;

j) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 64, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 91, respectively;

k) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 65, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 92, respectively;

l) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 52, 53 and 66, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 93, respectively;

m) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 67, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 94, respectively;

n) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 69, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 96, respectively;

o) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 70, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 97, respectively;

p) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 71, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80 and 98, respectively;

q) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 72, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 99, respectively;

r) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 73, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 100, respectively;

s) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 52, 53 and 74, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 101, respectively;

t) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 75, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 102, respectively;

u) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 76, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 103, respectively;

V a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 77, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 104, respectively; or

w) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 51, 53 and 78, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 79, 80 and 105, respectively.

2 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , comprising:

a) a variable heavy chain (VH) comprising an amino acid sequence of SEQ ID NO: 2 and a variable light chain (VL) comprising an amino acid sequence of SEQ ID NO: 27;

b) a VH comprising an amino acid sequence of SEQ ID NO: 3 and a VL comprising an amino acid sequence of SEQ ID NO: 28;

c) a VH comprising an amino acid sequence of SEQ ID NO: 4 and a VL comprising an amino acid sequence of SEQ ID NO: 29;

d) a VH comprising an amino acid sequence of SEQ ID NO: 5 and a VL comprising an amino acid sequence of SEQ ID NO: 30;

e) a VH comprising an amino acid sequence of SEQ ID NO: 6 and a VL comprising an amino acid sequence of SEQ ID NO: 31;

f) a VH comprising an amino acid sequence of SEQ ID NO: 7 and a VL comprising an amino acid sequence of SEQ ID NO: 32;

g) a VH comprising an amino acid sequence of SEQ ID NO: 8 and a VL comprising an amino acid sequence of SEQ ID NO: 33;

h) a VH comprising an amino acid sequence of SEQ ID NO: 9 and a VL comprising an amino acid sequence of SEQ ID NO: 34;

i) a VH comprising an amino acid sequence of SEQ ID NO: 10 and a VL comprising an amino acid sequence of SEQ ID NO: 35;

j) a VH comprising an amino acid sequence of SEQ ID NO: 11 and a VL comprising an amino acid sequence of SEQ ID NO: 36;

k) a VH comprising an amino acid sequence of SEQ ID NO: 12 and a VL comprising an amino acid sequence of SEQ ID NO: 37;

l) a VH comprising an amino acid sequence of SEQ ID NO: 13 and a VL comprising an amino acid sequence of SEQ ID NO: 38;

m) a VH comprising an amino acid sequence of SEQ ID NO: 14 and a VL comprising an amino acid sequence of SEQ ID NO: 39;

n) a VH comprising an amino acid sequence of SEQ ID NO: 16 and a VL comprising an amino acid sequence of SEQ ID NO: 41;

o) a VH comprising an amino acid sequence of SEQ ID NO: 17 and a VL comprising an amino acid sequence of SEQ ID NO: 42;

p) a VH comprising an amino acid sequence of SEQ ID NO: 18 and a VL comprising an amino acid sequence of SEQ ID NO: 43;

q) a VH comprising an amino acid sequence of SEQ ID NO: 19 and a VL comprising an amino acid sequence of SEQ ID NO: 44;

r) a VH comprising an amino acid sequence of SEQ ID NO: 20 and a VL comprising an amino acid sequence of SEQ ID NO: 45;

s) a VH comprising an amino acid sequence of SEQ ID NO: 21 and a VL comprising an amino acid sequence of SEQ ID NO: 46;

t) a VH comprising an amino acid sequence of SEQ ID NO: 22 and a VL comprising an amino acid sequence of SEQ ID NO: 47;

u) a VH comprising an amino acid sequence of SEQ ID NO: 23 and a VL comprising an amino acid sequence of SEQ ID NO: 48;

v) a VH comprising an amino acid sequence of SEQ ID NO: 24 and a VL comprising an amino acid sequence of SEQ ID NO: 49; or

w) a VH comprising an amino acid sequence of SEQ ID NO: 25 and a VL comprising an amino acid sequence of SEQ ID NO: 50.

3 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises an amino acid residue other than serine at position 74 according to the IMGT kappa variable light chain sequence numbering system.

4 . The anti-TCR delta variable 1 (anti-Vδ1) antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof when incubated with a viable Vδ1 T+ cell population causes a depletion of less than about 30%, or less than about 20%, or less than about 10% of the viable Vδ1 T+ cell population as measured via ADCC and/or CDC.

5 . The anti-TCR delta variable 1 (anti-Vδ1) antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to human TRVD1 with a KD of less than about 10 nM.

6 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof:

a) binds to human TRDV1 (SEQ ID NOs 272 or 306) with a binding affinity (KD) of less than about 100 nM as measured by surface plasmon resonance;

b) has an IC50 for TCR downregulation of less than about 50 nM;

c) has an IC50 for THP-1 cell killing of less than about 10 nM; and

has an IC90 for THP-1 cell killing of less than about 50 nM.

7 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the epitope bound by the antibody or antigen-binding fragment thereof is an activating epitope of a γδ T cell.

8 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is an IgG antibody.

9 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is not a bispecific antibody or a multispecific antibody.

10 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is Fc enabled.

11 . A pharmaceutical composition comprising the antibody or antibody binding fragment thereof as defined in claim 1 and a pharmaceutically acceptable diluent or carrier.

12 . A method of treating a disease or disorder in a subject or a method of modulating an immune response in a subject, comprising administering to the subject an anti-Vδ1 antibody or antibody binding fragment of claim 1 .

13 . The method of claim 12 , wherein the disease or disorder is cancer, an infectious disease or an inflammatory disease, or wherein the subject in which an immune response is modulated has cancer, an infectious disease, or an inflammatory disease or wherein modulating an immune response in a subject comprises at least one of, activating γδ T cells, causing or increasing proliferation γδ T cells, causing or increasing expansion of γδ T cells, causing or increasing γδ T cell degranulation, causing or increasing γδ T cell mediated killing activity, causing or increasing γδ T cytotoxicity, causing or increasing γδ T cell mobilization, increasing survival of γδ T cells, and increasing resistance to exhaustion of γδ T cells.

14 . The method of claim 12 , wherein diseased cells are killed while healthy cells are spared.

15 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 3 , wherein the residue at position 74 according to the IMGT numbering system is a leucine residue.

16 . An anti-TCR delta variable 1 (anti-Vδ1) antibody or antigen-binding fragment thereof comprising:

a heavy chain variable region (VH) comprising:

a VHCDR1 comprising an amino acid sequence of SEQ ID NO: 130;

a VHCDR2 comprising an amino acid sequence of: SEQ ID NO: 131; and

a VHCDR3 comprising an amino acid sequence of any one of: SEQ ID NO: 133 to 143; and

a light chain variable region (VL) comprising:

a VLCDR1 comprising an amino acid sequence of SEQ ID NO: 144;

a VLCDR2 comprising an amino acid sequence of SEQ ID NO: 145; and

a VLCDR3 comprising an amino acid sequence of any one of: SEQ ID NO: 147 to 157.

17 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 16 , wherein:

a) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 133, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 147, respectively;

b) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 134, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 148, respectively;

c) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 135, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 149, respectively;

d) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 136, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 150, respectively;

e) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 137, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 151, respectively;

f) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 138, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 152, respectively;

g) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 139, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 153, respectively;

h) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 140, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 154, respectively;

i) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 141, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 155, respectively;

j) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 142, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 156, respectively; or

k) a VHCDR1, a VHCDR2 and a VHCDR3 comprising the amino acid sequences of SEQ ID NO: 130, 131 and 143, respectively, and a VLCDR1, a VLCDR2 and a VLCDR3 comprising the amino acid sequences of SEQ ID NO: 144, 145 and 157, respectively.

18 . The anti-TCR delta variable 1 (anti-Vδ1) antibody or antigen-binding fragment thereof of claim 16 , comprising: a heavy chain variable region (VH) comprising a sequence of any one of SEQ ID NO: 107 to 117; and a light chain variable region (VL) comprising a sequence of any one of SEQ ID NO: 119 to 129.

19 . The anti-Vδ1 antibody or antigen-binding fragment thereof of claim 16 , comprising:

a) a VH comprising an amino acid sequence of SEQ ID NO: 107 and a VL comprising an amino acid sequence of SEQ ID NO: 119;

b) a VH comprising an amino acid sequence of SEQ ID NO: 108 and a VL comprising an amino acid sequence of SEQ ID NO: 120;

c) a VH comprising an amino acid sequence of SEQ ID NO: 109 and a VL comprising an amino acid sequence of SEQ ID NO: 121;

d) a VH comprising an amino acid sequence of SEQ ID NO: 110 and a VL comprising an amino acid sequence of SEQ ID NO: 122;

e) a VH comprising an amino acid sequence of SEQ ID NO: 111 and a VL comprising an amino acid sequence of SEQ ID NO: 123;

f) a VH comprising an amino acid sequence of SEQ ID NO: 112 and a VL comprising an amino acid sequence of SEQ ID NO: 124;

g) a VH comprising an amino acid sequence of SEQ ID NO: 113 and a VL comprising an amino acid sequence of SEQ ID NO: 125;

h) a VH comprising an amino acid sequence of SEQ ID NO: 114 and a VL comprising an amino acid sequence of SEQ ID NO: 126;

i) a VH comprising an amino acid sequence of SEQ ID NO: 115 and a VL comprising an amino acid sequence of SEQ ID NO: 127;

j) a VH comprising an amino acid sequence of SEQ ID NO: 116 and a VL comprising an amino acid sequence of SEQ ID NO: 128; or

k) a VH comprising an amino acid sequence of SEQ ID NO: 117 and a VL comprising an amino acid sequence of SEQ ID NO: 129.

20 . A method of treating a disease or disorder in a subject or a method of modulating an immune response in a subject, comprising administering to the subject an anti-Vδ1 antibody or antibody binding fragment of claim 16 .

21 . The method of claim 20 , wherein the disease or disorder is cancer, an infectious disease or an inflammatory disease, or wherein the subject in which an immune response is modulated has cancer, an infectious disease, or an inflammatory disease or wherein modulating an immune response in a subject comprises at least one of, activating γδ T cells, causing or increasing proliferation γδ T cells, causing or increasing expansion of γδ T cells, causing or increasing γδ T cell degranulation, causing or increasing γδ T cell mediated killing activity, causing or increasing γδ T cytotoxicity, causing or increasing γδ T cell mobilization, increasing survival of γδ T cells, and increasing resistance to exhaustion of γδ T cells.