NOVEL HUMAN ANTIBODIES BINDING TO HUMAN CD3 EPSILON

1 : An isolated human antibody or antibody fragment specific for human CD3 epsilon, wherein said antibody or antibody fragment comprises:

a) an HCDR1 region comprising the amino acid sequence of GFTFX 1 SX 2 X 3 MX 4 , wherein X 1 is S, K or R; X 2 is Y or H; X 3 is W or Y; and X 4 is S or T (SEQ ID NO: 90);

b) an HCDR2 region comprising the amino acid sequence of NIX 1 X 2 X 3 X 4 X 5 X 6 X 7 YYX B X 9 SVKG, wherein X 1 is K or D; X 2 is Q or Y; X 3 is D, Q or E; X 4 is S or G; X 5 is S, Q or T; X 6 is E, H or R; X 7 is K, A or T; X 8 is V or A; and X 9 is D or E (SEQ ID NO: 91);

c) an HCDR3 region comprising the amino acid sequence of GYSAEFAHRSGLDV (SEQ ID NO: 39);

d) a LCDR1 region comprising the amino acid sequence of SGSSSNIGX 1 X 2 YVY, wherein X 1 is S, I, A, K or Q; and X 2 is N or T (SEQ ID NO: 92);

e) a LCDR2 region comprising the amino acid sequence of RNX 1 X 2 RPS, wherein X 1 is N, K, S, H, T or Y; and X 2 is Q, I or K (SEQ ID NO: 93); and

f) a LCDR3 region comprising the amino acid sequence of AX 1 WDX 2 X 3 X 4 X 5 GAV, wherein X 1 is A or G; X 2 is H or R; X 3 is H or R; X 4 is R, S or L; and X 5 is S or H (SEQ ID NO: 94).

2 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment comprises:

a) an HCDR1 region comprising the amino acid sequence of GFTFSSYWMS (SEQ ID NO: 40), GFTFKSYYMS (SEQ ID NO: 41) or GFTFRSHYMT (SEQ ID NO: 42);

b) an HCDR2 region comprising the amino acid sequence of NIKQDGSEKYYVDSVKG (SEQ ID NO: 43), NIDYQSQHAYYAESVKG (SEQ ID NO: 44) or NIDYEGTRTYYAESVKG (SEQ ID NO: 45);

c) an HCDR3 region comprising the amino acid sequence of GYSAEFAHRSGLDV (SEQ ID NO: 39);

d) a LCDR1 region comprising the amino acid sequence of SGSSSNIGSNYVY (SEQ ID NO: 46), SGSSSNIGINYVY (SEQ ID NO: 47), SGSSSNIGANYVY (SEQ ID NO: 48), SGSSSNIGQTYVY (SEQ ID NO: 49), or SGSSSNIGKNYVY (SEQ ID NO: 50);

e) a LCDR2 region comprising the amino acid sequence of RNNQRPS (SEQ ID NO: 51), RNNIRPS (SEQ ID NO: 52), RNNKRPS (SEQ ID NO: 53), RNKKRPS (SEQ ID NO: 54), RNKQRPS (SEQ ID NO: 55), RNSQRPS (SEQ ID NO: 56), RNHIRPS (SEQ ID NO: 57), RNTQRPS (SEQ ID NO: 58), or RNYQRPS (SEQ ID NO: 59); and

f) a LCDR3 region comprising the amino acid sequence of AAWDHHRSGAV (SEQ ID NO: 60), AAWDRHSHGAV (SEQ ID NO: 61) or AGWDRRLHGAV (SEQ ID NO: 62).

3 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment comprises a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15.

4 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment comprises a variable light chain (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38.

5 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment comprises

a) a variable heavy chain (VH) comprising the amino acid sequence of SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15; and

b) a variable light chain (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38.

6 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein the variable heavy chain and variable light chain are selected from the group consisting of:

a) the VH comprising the amino acid sequence of SEQ ID NO: 13 and the VL comprising the amino acid sequence of SEQ ID NO: 16,

b) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 16,

c) the VH comprising the amino acid sequence of SEQ ID NO: 13 and the VL comprising the amino acid sequence of SEQ ID NO: 17,

d) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 17,

e) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 18,

f) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 19,

g) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 20,

h) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 21,

i) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 22,

j) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 23,

k) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 24,

l) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 25,

m) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 26,

n) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 27,

o) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 28,

p) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 29,

q) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 30,

r) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 31,

s) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 32,

t) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 33,

u) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 34,

v) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 35,

w) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 36,

x) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 37,

y) the VH comprising the amino acid sequence of SEQ ID NO: 14 and the VL comprising the amino acid sequence of SEQ ID NO: 38,

z) the VH comprising the amino acid sequence of SEQ 1D NO: 15 and the VL comprising the amino acid sequence of SEQ 1D NO: 17,

aa) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 18,

bb) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 19,

cc) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 20,

dd) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 21,

ee) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 22,

ff) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 23,

gg) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 24,

hh) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 25,

ii) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 26,

jj) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 27,

kk) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 28,

ll) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 29,

mm) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 30,

nn) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 31,

oo) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 32,

pp) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 33,

qq) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ 1D NO: 34,

rr) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 35,

ss) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 36,

tt) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 37, and

uu) the VH comprising the amino acid sequence of SEQ ID NO: 15 and the VL comprising the amino acid sequence of SEQ ID NO: 38.

7 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment cross-reactively binds to cynomolgus CD3 epsilon.

8 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment is a recombinant antibody or antibody fragment.

9 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein said antibody or antibody fragment is a monoclonal antibody or antibody fragment.

10 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein the antibody fragment is selected from the group consisting of a Fab, Fv, and scFv.

11 : The isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 , wherein the antibody is an IgG.

12 : A multispecific antibody comprising the isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 .

13 : The multispecific antibody according to claim 12 , wherein the multispecific antibody also specifically binds to a cancer associated antigen.

14 : A pharmaceutical composition comprising the isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 and a pharmaceutically acceptable carrier or excipient.

15 . (canceled)

16 : A pharmaceutical composition comprising the multispecific antibody according to claim 12 and a pharmaceutically acceptable carrier or excipient.

17 : A method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 to the subject.

18 : A method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the multispecific antibody according to claim 12 to the subject.