Bispecific heterodimeric diabodies and uses thereof

1. A bispecific heterodimeric diabody that specifically binds to an epitope of human P-cadherin and to an epitope of CD3 comprising a first polypeptide chain and a second polypeptide chain, wherein:

a. the first polypeptide comprises, in the N-terminal to C-terminal direction:

i. a Domain 1, comprising a sub-Domain 1A and a sub-Domain 1B, and

ii. a first heterodimer-promoting domain; and

b. the second polypeptide chain comprises, in the N-terminal to C-terminal direction:

i. a Domain 2, comprising a sub-Domain 2B and a sub-Domain 2A and

ii. a second heterodimer-promoting domain, and

wherein sub-Domain 1A and sub-Domain 2A form a P-cadherin VL/VH binding domain comprising a variable heavy (VH) domain of an anti-P-cadherin antibody (P-CAD VH) and a variable light (VL) domain of an anti-P-cadherin antibody (P-CAD VL), and sub-Domain 1B and sub-Domain 2B form a CD3 VL/VH binding domain comprising a VL domain of an anti-CD3 antibody (CD3 VL) and a VH binding domain of an anti-CD3 antibody (CD3 VH); or

wherein sub-Domain 1A and sub-Domain 2A form a CD3 VL/VH binding domain comprising a CD3 VL and a CD3 VH, and sub-Domain 1B and sub-Domain 2B form a P-cadherin VL/VH binding domain comprising a P-CAD VH and a P-CAD VL; and

wherein the first and second polypeptide chains comprise:

i. a P-CAD VL CDR1, a P-CAD VL CDR2, and a P-CAD VL CDR3 of a P-CAD VL comprising a sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 or 23;

ii. a CD3 VH CDR1, a CD3 VH CDR2, and a CD3 VH CDR3 of a CD3 VH comprising a sequence of SEQ ID NO: 45 or 46;

iii. a CD3 VL CDR1, a CD3 VL CDR2, and a CD3 VL CDR3 of a CD3 VL comprising a sequence of SEQ ID NO: 47; and/or

iv. a P-CAD VH CDR1, a P-CAD VH CDR2, and a P-CAD VH CDR3 of a P-CAD VH comprising a sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24;

c. the sub-Domain 1A and the sub-Domain 1B are linked by a glycine-serine linker (Linker 1), and the sub-Domain 2B and the sub-Domain 2A are linked by a glycine-serine linker (Linker 1);

d. the first heterodimer-promoting domain comprises a cysteine linker (Linker 2) on sub-Domain 1B and/or the second heterodimer-promoting domain comprises a cysteine linker (Linker 2) on sub-Domain 2A; and

e. the first and second polypeptide chains are covalently bonded to one another by at least one disulfide bond.

2. The bispecific heterodimeric diabody of claim 1 , wherein the sub-Domain 1A comprises a P-CAD VL or a CD3 VL, and the sub-Domain 1B comprises a P-CAD VH if the sub-Domain 1A comprises CD3 VL or the sub-Domain 1B comprises a CD3 VH if the sub-Domain 1A comprises P-CAD VL; and wherein the sub-Domain 2B comprises a P-CAD VL or a CD3 VL depending on the VL domain selected for sub-Domain 1A, and the sub-Domain 2A comprises P-CAD VH if the sub-Domain 2B comprises CD3 VL or the sub-Domain 2A comprises a CD3 VH if the sub-Domain 2B comprises P-CAD VL.

3. The bispecific heterodimeric diabody of claim 1 , wherein the sub-Domain 1A comprises a P-CAD VL and the sub-Domain 1B comprises a CD3 VH, and the sub-Domain 2B comprises a CD3 VL and the sub-Domain 2A comprises a P-CAD VH.

4. The bispecific heterodimeric diabody of claim 1 , wherein the sub-Domain 1A comprises a CD3 VL and the sub-Domain 1B comprises a P-CAD VH, and the sub-Domain 2B comprises a P-CAD VL and the sub-Domain 2A a CD3 VH.

5. The bispecific heterodimeric diabody of claim 1 , wherein the sub-Domain 1A comprises a P-CAD VH or a CD3 VH, and the sub-Domain 1B comprises a P-CAD VL if the sub-Domain 1A comprises CD3 VH or the sub-Domain 1B comprises a CD3 VL if the sub-Domain 1A comprises a P-CAD VH; and wherein the sub-Domain 2B comprises a P-CAD VH or a CD3 VH depending on the VH domain selected for sub-Domain 1A, and the sub-Domain 2A comprises P-CAD VL if the sub-Domain 2B comprises a CD3 VH or the sub-Domain 2A comprises a CD3 VL if the sub-Domain 2B comprises a P-CAD VH.

6. The bispecific heterodimeric diabody of claim 1 or 5 , wherein the sub-Domain 1A comprises a P-CAD VH and the sub-Domain 1B comprises a CD3 VL, and the sub-Domain 2B comprises a CD3 VH and the sub-Domain 2A comprises a P-CAD VL.

7. The bispecific heterodimeric diabody of claim 1 or 5 , wherein the sub-Domain 1A comprises a CD3 VH and the sub-Domain 1B comprises a P-CAD VL, and the sub-Domain 2B comprises a P-CAD VH and the sub-Domain 2A comprises a CD3 VL.

8. The bispecific heterodimeric diabody of claim 1 , wherein the first heterodimer-promoting domain and the second heterodimer-promoting domain comprise an IgG Fc region comprising a CH2 and a CH3 domain, wherein the amino acid sequence of the CH2 domain and/or the CH3 domain comprises at least one amino acid modification, as compared to a wild-type IgG Fc region, to form a knob or a hole.

9. The bispecific heterodimeric diabody of claim 8 , wherein the first heterodimer-promoting domain and the second heterodimer-promoting domain are not both knobs or both holes; and/or wherein the first heterodimer-promoting domain and the second heterodimer-promoting domain form an IgG immunoglobulin Fc region.

10. The bispecific heterodimeric diabody of claim 9 , wherein the IgG Fc region forming the knob comprises a sequence of SEQ ID NO: 63, and the IgG Fc region forming the hole comprises a sequence of SEQ ID NO: 64.

11. The bispecific heterodimeric diabody of claim 1 , wherein the glycine-serine linker (Linker 1) comprises a sequence of SEQ ID NO: 68 or SEQ ID NO: 69.

12. The bispecific heterodimeric diabody of claim 1 , wherein the sub-Domain 1A and the sub-Domain 1B do not associate to form a VL/VH epitope binding domain, and the sub-Domain 2B and the sub-Domain 2A do not associate to form a VL/VH epitope binding domain.

13. The bispecific heterodimeric diabody of claim 1 , wherein the Linker 2 of the first heterodimer-promoting domain and/or the second heterodimer-promoting domain further comprises at least one glycine residue.

14. The bispecific heterodimeric diabody of claim 13 , wherein the Linker 2 of the first heterodimer-promoting domain and/or the second heterodimer-promoting domain comprises a sequence of GFNRGEC (SEQ ID NO: 70), GVEPKSC (SEQ ID NO: 71), GGCGGG (SEQ ID NO: 72), GCPPCP (SEQ ID NO: 73), GGTGGCPPCP (SEQ ID NO: 74), GEPKSSDKTHTCPPCP (SEQ ID NO: 75) or GGTGGGEPKSSDKTHTCPPCP (SEQ ID NO: 76).

15. The bispecific heterodimer diabody of claim 14 , wherein the Linker 2 of the first heterodimer-promoting domain comprises the sequence of GCPPCP (SEQ ID NO: 73), GGTGGCPPCP (SEQ ID NO: 74), GEPKSSDKTHTCPPCP (SEQ ID NO: 75) or GGTGGGEPKSSDKTHTCPPCP (SEQ ID NO: 76), and the Linker 2 of the second heterodimer-promoting domain comprises the sequence of GCPPCP (SEQ ID NO: 73), GGTGGCPPCP (SEQ ID NO: 74), GEPKSSDKTHTCPPCP (SEQ ID NO: 75) or GGTGGGEPKSSDKTHTCPPCP (SEQ ID NO: 76).

16. The bispecific heterodimer diabody of claim 14 , wherein the Linker 2 of the first heterodimer-promoting domain comprises the sequence of GGCGGG (SEQ ID NO: 72), and the Linker 2 of the second heterodimer-promoting domain comprises the sequence of GGCGGG (SEQ ID NO: 72).

17. The bispecific heterodimeric diabody of claim 14 , wherein the Linker 2 of the first heterodimer-promoting domain comprises the sequence of GFNRGEC (SEQ ID NO: 70) and the Linker 2 of the second heterodimer-promoting domain comprises the sequence of GVEPKSC (SEQ ID NO: 71), or the Linker 2 of the first heterodimer-promoting domain comprises the sequence of GVEPKSC (SEQ ID NO: 71) and the Linker 2 of the second heterodimer-promoting domain comprises the sequence of GFNRGEC (SEQ ID NO: 70).

18. The bispecific heterodimeric diabody of claim 1 , wherein the bispecific heterodimeric diabody:

a. binds to extracellular domain 3 (ECD3) of human P-cadherin,

b. binds to an epitope on human P-cadherin but does not bind to an epitope on E-cadherin or VE-cadherin, or

c. demonstrates a lower EC50 in the presence of increased human P-cadherin expression levels or increased human P-cadherin receptor density levels.

19. A bispecific heterodimer diabody that specifically binds to an epitope of P-cadherin and to an epitope of CD3 comprising a first polypeptide chain and a second polypeptide chain, wherein:

a. the first polypeptide chain comprises, in the N-terminal to C-terminal direction:

i. a Domain 1, comprising a sub-Domain 1A and a sub-Domain 1B, and

ii. a first heterodimer-promoting domain; and

b. the second polypeptide chain comprises, in the N-terminal to C-terminal direction:

i. a Domain 2, comprising a sub-Domain 2B and a sub-Domain 2A and

ii. a second heterodimer-promoting domain, and

wherein sub-Domain 1A and sub-Domain 2A form a P-cadherin VL/VH binding domain comprising a variable heavy (VH) domain of an anti-P-cadherin antibody (P-CAD VH) and a variable light (VL) domain of an anti-P-cadherin antibody (P-CAD VL), and sub-Domain 1B and sub-Domain 2B form a CD3 VL/VH binding domain comprising a VL domain of an anti-CD3 antibody (CD3VL) and a VH binding domain of an anti-CD3 antibody (CD3 VH); or

wherein sub-Domain 1A and sub-Domain 2A form a CD3 VL/VH binding domain comprising a CD3 VL and a CD3 VH, and sub-Domain 1B and sub-Domain 2B form a P-cadherin VL/VH binding domain comprising a P-CAD VH and a P-CAD VL; and

wherein the polypeptide chain comprises:

i. a P-CAD VL CDR1 sequence comprising X L1.1 -X L1.2 -X L1.3 -X L1.4 -X L1.6 -X L1.7 -X L1.8 -X L1.9 -X L1.10 -X L1.11 -X L1.12 -X L1.13 , wherein

X L1.1 is W, C, I, F, Y, T, H, N, M, Q, K, L, S, A, V, D, R, E, or G,

X L1.2 is G,

X L1.3 is R, Q, Y, L, K, F, M, N, W, C, I, T, V, S, E, A, H, D, or G,

X L1.4 is C, L, F, S, I, T, W, N, Y, V, D, A, K, Q, M, H, or R,

X L1.5 is F, C, I, T, V, N, H, L, Y, S, R, Q, W, A, M, E, K, or D,

X L1.6 is L, Q, F, M, N, C, K, H, or T,

X L1.7 is I, Q, H, F, L, or V,

X L1.8 is R, Q, L, T, G, C, E, D, M, Y, or S,

X L1.9 is C, W, I, L, F, R, V, T, K, N, S, M, Q, Y, E, A, H, or D,

X L1.10 is Q, F, N, L, C, Y, H, R, W, or M,

X L1.11 is M, H, K, V, Q, L, Y, C, I, N, F, T, S, E, or W,

X L1.12 is I, N, V, L, C, or T,

X L1.13 is W, R, F, K, I, H, V, C, T, L, N, M, Q, Y, S, A, D, or E,

ii. a P-CAD VL CDR2 sequence comprising X L2.1 -X L2.2 -X L2.3 -X L2.4 -X L2.5 -X L2.6 -X L2.7 , wherein

X L2.1 is I, L, V, F, Y, W, C, R, Q, N, M, H, E, T, P, K, D, S, A, or G,

X L2.2 is W, L, F, I, C, N, R, V, Q, Y, E, D, H, or M,

N L2.3 is C, Q, L, F, Y, W, E, R, M, H, A, N, T, K, D, S, I, V, or G,

X L2.4 is R, K, L, C, Q, V, W, Y, M, F, or H,

X L2.5 is R, Q, L, W, K, or H,

X L2.6 is R, K, I, W, F, L, Q, C, M, Y, H, V, N, T, A, E, S, P, or D,

X L2.7 is C, L, T, S, K, M, R, V, F, P, A, W, Q, D, N, G, or Y,

iii. a P-CAD VL CDR3 X L3.1 -X L3.2 -X L3.3 -X L3.4 -X L3.5 -X L3.6 -X L3.7 -X L3.8 -X L3.9 -X L3.10 -X L3.11 , wherein

X L3.1 is W, R, Y, F, L, N, Q, C, M, I, H, T, A, D, E, S, K, V, or G,

X L3.2 is N, C, V, T, S, or A,

X L3.3 is W,

X L3.4 is F, N, D, E, H, Q, Y, R, or W,

X L3.5 is T, R, L, C, F, Y, W, Q, M, H, E, N, V, S, D, K, or A,

X L3.6 is I, H, C, M, N, L, V, Q, E, S, T, A, K, D, F, Y, G, R, or W,

X L3.7 is L, C, R, I, H, Q, E, T, V, M, K, F, or Y,

X L3.8 is W, L, C, F, T, N, V, Y, M, H, Q, S, K, E, D, A, R, or G,

X L3.9 is L, Y, Q, F, H, C, R, M, N, D, W, E, K, T, V, A, S, or G,

X L3.10 is I, F, K, L, H, Y, M, V, Q, W, T, N, or C,

X L3.11 is Q, W, R, F, T, C, Y, V, E, L, N, I, K, or M,

iv. a P-CAD VH CDR1 sequence comprising X H1.1 -X H1.2 -X H1.3 -X H1.4 , X H1.5 -X H1.6 -X H1.7 -X H1.8 -X H1.9 -X H1.10 or X H1.5 -X H1.6 -X H1.7 -X H1.8 -X H1.9 -X H1.10 , wherein

X H1.1 is R, Q, I, LC, F, T, G, V, W, M, Y, N, E, P, K, H, D, S, or A,

X H1.2 is H, R, C, Q, Y, I, F, K, M, V, L, N, or T,

X H1.3 is N, C, R, V, L, T, I, S, K, Q, M, W, A, F, Y, H, or D,

X H1.4 is F or Y,

X H1.5 is W, R, I, C, K, Y, M, V, F, T, S, L, Q, E, A, N, H, D, or G,

X H1.6 is R, I, M, N, Y, C, H, Q, L, K, F, V, T, E, A, 5, D, W, or G,

X H1.7 is K, R, L, H, F, Q, N, C, Y, M, I, T, V, or A,

X H1.8 is P, R, F, W, H, C, Y, 1, M, K, G, S, Q, A, L, N, T, or D,

X H1.9 is Y, F, K, I, W, or L,

X H1.10 is R, C, L, N, 5, V, T, or A,

v. P-CAD VH CDR2 sequence comprising X H2.1 -X H2.2 -X H2.3 -X H2.4 -X H2.5 -X H2.6 -X H2.7 -X H2.8 -X H2.9 -X H2.10 or X H2.1 -X H2.2 -X H2.3 -X H2.4 -X H2.5 -X H2.6 -X H2.7 -X H2.8 -X H2.9 -X H2.10 -X H2.11 -X H2.12 -X H2.13 -X H2.14 -X H2.15 -X H2.16 -X H2.17 wherein

X H2.1 is W,

X H2.2 is W, F, Y, I, V, H, L, or Q,

X H2.3 is W, F, L, R, C, H, T, N, Y, Q, K, A, I, V, S, M, E, or D,

X H2.4 is I, Y, V, Q, F, H, K, C, N, T, E, L, M, D, P, S, A, or W,

X H2.5 is C, P, T, S, L, V, M, F, W, Q, K, G, I, A, N, H, E, D, Y, R,

X H2.6 is I, Q, W, V, C, L, K, E, T, M, F, Y, R, S, A, N, H, D, or G,

X H2.7 is G, C, L, N, W, F, S, Y, T, D, I, or M,

X H2.8 is Q, C, I, Y, W, L, T, V, K, M, H, F, S, R, A, E, N, D, or G,

X H2.9 is F, L, V, W, H, C, Y, K, I, Q, R, T, M, N, A, S, or D,

X H2.10 is R, W, K, F, C, T, L, Y, N, Q, V, H, M, A, S, or D,

X H2.11 is L, F, W, N, Y, H, K, R, I, M, V, C, Q, or E,

X H2.12 is W, F, I, Y, L, R, V, M, H, N, C, Q, K, T, D, E, A, or S,

X H2.13 is P, R, Q, C, T, I, W, F, K, L, Y, S, V, M, D, or H,

X H2.14 is W, C, I, F, T, R, Y, L, Q, S, V, D, N, M, K, A, H, E, or G,

X H2.15 is W, L, V, F, K, R, H, Y, or M,

X H2.16 is W, F, C, T, L, R, N, A, S, M, K, E, H, Y, or G,

X H2.17 is P, G, T, M, C, E, or V,

and

vi. a P-CAD VH CDR3 sequence comprising X H3.1 -X H3.2 -X H3.3 -X H3.4 -X H3.5 -X H3.6 -X H3.7 -X H3.8 -X H3.9 , wherein

X H3.1 is F, Y, I, R, W, or L,

N H3.2 is F, I, C, M, W, Q, L, H, V, N, R, T, D, S, E, A, Y, or K,

X H3.3 is H, W, C, I, S, L, T, F, Q, Y, V, A, M, K, N, G, D, or E,

X H3.4 is Y, I, M, W, R, H, V, F, C, K, N, Q, L, D, T, S, A, or E,

X H3.5 is W, L, V, I, P, C, Y, M, H, T, N, F, D, A, or S,

X H3.6 is F, W, C, H, N, R, Y, L, A, Q, E, M, T, I, S, K, or D,

X H3.7 is Y, F, or W,

X H3.8 is W, F, Y, I, L, Q, R, H, M, N, V, C, T, K, E, D, S, A, P, or G,

X H3.9 is W, Y, F, R, I, L, C, V, H, N, K, T, Q, M, or D;

c. the sub-Domain 1A and the sub-Domain 1B are linked by a glycine-serine linker (Linker 1), and the sub-Domain 2B and the sub-Domain 2A are linked by a glycine-serine linker (Linker 1);

d. the first heterodimer-promoting domain comprises a cysteine linker (Linker 2) on sub-Domain 1B and/or the second heterodimer-promoting domain comprises a cysteine linker (Linker 2) on sub-Domain 2A; and

e. the first and second polypeptide chains are covalently bonded to one another by at least one disulfide bond.

20. The bispecific heterodimer diabody of claim 19 , wherein X L3.3 is W, X H2.5 is Y, X H3.1 is I, X H3.7 is F, X L1.8 is G, X L2.2 is N, X L2.3 is N, X L3.2 is T, X H2.6 is N, X H2.16 is Q, X H3.5 is N and X H3.9 is I.

21. The bispecific heterodimer diabody of claim 19 , wherein X L3.3 is W, X H1.8 is G, X H2.5 is Y, X H3.1 is I, and X H3.7 is F.

22. The bispecific heterodimeric diabody of claim 19 , comprising:

a. a P-CAD VL CDR1, a P-CAD VL CDR2, and a P-CAD VL CDR3 of a P-CAD VL comprising a sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 or 23;

b. a CD3 VH CDR1, a CD3 VH CDR2, and a CD3 VH CDR3 of a CD3 VH comprising a sequence of SEQ ID NO: 45 or 46;

c. a CD3 VL CDR1, a CD3 VL CDR2, and a CD3 VL CDR3 of a CD3 VL comprising a sequence of SEQ ID NO: 47; and/or

d. a P-CAD VH CDR1, a P-CAD VH CDR2, and a P-CAD VH CDR3 of a P-CAD VH comprising a sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24.

23. The bispecific heterodimeric diabody of claim 1 or 22 , wherein:

a. the P-CAD VL CDR1 comprises a sequence of SEQ ID NO: 35 or 36, the P-CAD VL CDR2 comprises a sequence of SEQ ID NO: 37 or 38, and the P-CAD VL CDR3 comprises a sequence of SEQ ID NO: 39, 40, 41, 42, 43 or 44;

b. the CD3 VH CDR1 comprises a sequence of SEQ ID NO: 48, 52 or 53, the CD3 VH CDR2 comprises a sequence of SEQ ID NO: 49, 50 or 54, and the CD3 VH CDR3 comprises a sequence of SEQ ID NO: 51;

c. the CD3 VL CDR1 comprises a sequence of SEQ ID NO: 55, the CD3 VL CDR2 comprises a sequence of SEQ ID NO: 56, and the CD3 VL CDR3 comprises a sequence of SEQ ID NO: 57; and/or

d. the P-CAD VH CDR1 comprises a sequence of SEQ ID NO: 25 or 33, the P-CAD VH CDR2 comprises a sequence of SEQ ID NO: 26 or 34, and a P-CAD VH CDR3 comprising a sequence of SEQ ID NO: 27, 28, 29, 30, 31 or 32.

24. The bispecific heterodimeric diabody of claim 23 , wherein the P-CAD VL CDR1 comprises the sequence of SEQ ID NO: 35, the P-CAD VL CDR2 comprises the sequence of SEQ ID NO: 37, the P-CAD VL CDR3 comprises the sequence of SEQ ID NO: 41, the P-CAD VH CDR1 comprises the sequence of SEQ ID NO: 25, the P-CAD VH CDR2 comprises the sequence of SEQ ID NO: 26, and the P-CAD VH CDR3 comprises the sequence of SEQ ID NO: 28.

25. The bispecific heterodimeric diabody of claim 23 , wherein the P-CAD VL CDR1 comprises the sequence of SEQ ID NO: 35; the P-CAD VL CDR2 comprises the sequence of SEQ ID NO: 37; and the P-CAD VL CDR3 comprises the sequence of SEQ ID NO: 42, the P-CAD VH CDR1 comprises the sequence of SEQ ID NO: 25, the P-CAD VH CDR2 comprises the sequence of SEQ ID NO: 26, and the P-CAD VH CDR3 comprises the sequence of SEQ ID NO: 29.

26. The bispecific heterodimeric diabody of claim 23 , wherein the P-CAD VL CDR1 comprises the sequence of SEQ ID NO: 35; the P-CAD VL CDR2 comprises the sequence of SEQ ID NO: 37, the P-CAD VL CDR3 comprises the sequence of SEQ ID NO: 43, the P-CAD VH CDR1 comprises the sequence of SEQ ID NO: 25, the P-CAD VH CDR2 comprises the sequence of SEQ ID NO: 26, and the P-CAD VH CDR3 comprises the sequence of SEQ ID NO: 30.

27. The bispecific heterodimeric diabody of claim 23 , wherein the P-CAD VL CDR1 comprises the sequence of SEQ ID NO: 35; the P-CAD VL CDR2 comprises the sequence of SEQ ID NO: 37, the P-CAD VL CDR3 comprises the sequence of SEQ ID NO: 39, the P-CAD VH CDR1 comprises the sequence of SEQ ID NO: 25, the P-CAD VH CDR2 comprises the sequence of SEQ ID NO: 26, and the P-CAD VH CDR3 comprises the sequence of SEQ ID NO: 31.

28. The bispecific heterodimeric diabody of claim 23 , wherein:

a. the P-CAD VL comprises a sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21 or 23;

b. the CD3 VH comprises a sequence of SEQ ID NO: 45 or 46;

c. the CD3 VL comprises the sequence of SEQ ID NO: 47; and

d. the P-CAD VH comprises a sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24.

29. The bispecific heterodimeric diabody of claim 28 , wherein the P-CAD VL comprises the sequence of SEQ ID NO: 5, and the P-CAD VH comprises the sequence of SEQ ID NO: 6.

30. The bispecific heterodimeric diabody of claim 28 , wherein the P-CAD VL comprises the sequence of SEQ ID NO: 7, and the P-CAD VH comprises the sequence of SEQ ID NO: 8.

31. The bispecific heterodimeric diabody of claim 28 , wherein the P-CAD VL comprises the sequence of SEQ ID NO: 9 and the P-CAD VH comprises the sequence of SEQ ID NO: 10.

32. The bispecific heterodimeric diabody of claim 28 , wherein the P-CAD VL comprises the sequence of SEQ ID NO: 15 and the P-CAD VH comprises the sequence of SEQ ID NO: 16.

33. A bispecific heterodimeric diabody that specifically binds to an epitope of human P-cadherin and to an epitope of CD3 comprising a first polypeptide chain and a second polypeptide chain, wherein the first polypeptide chain comprises a sequence of SEQ ID NO: 90 and the second polypeptide chain comprises a sequence of SEQ ID NO: 91.

34. A pharmaceutical composition comprising: a therapeutically effective amount of the bispecific heterodimeric diabody of claim 1 , 23 , or 33 , and a pharmaceutically acceptable carrier.