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1. (WO2017136659) HUMANIZED ANTI-CD3 ANTIBODIES, CONJUGATES AND USES THEREOF
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CLAIMS

What is claimed is:

1. An antibody comprising: a first amino acid sequence comprising SEQ ID NO: 74, and a second amino acid sequence comprising one or more of SEQ ID NOS: 54-56.

2. The antibody of claim 1, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 51-53.

3. The antibody of claim 1 or claim 2, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 97, 59, or 110.

4. The antibody of any preceding claim, wherein the first amino acid sequence comprises SEQ ID NO: 32.

5. The antibody of any preceding claim, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 114-123.

6. The antibody of any preceding claim, wherein the first amino acid sequence comprises SEQ ID NO: 111 or 112.

7. The antibody of any preceding claim, wherein the second amino acid sequence comprises one or more of SEQ ID NOS: 87, 92, 96, or 124.

8. The antibody of any preceding claim, wherein the second amino acid sequence comprises SEQ ID NO: 27.

9. The antibody of any preceding claim, wherein the second amino acid sequence comprises one or more of SEQ ID NOS: 99-108.

10. The antibody of any preceding claim, wherein the second amino acid sequence comprises SEQ ID NO: 86 or 98.

11. The antibody of any preceding claim, wherein the first amino acid sequence comprises a light chain constant domain sequence, the second amino acid sequence comprises a light chain constant domain sequence, or both the first and the second amino acid sequence each comprises a light chain constant domain sequence.

12. The antibody of any preceding claim, wherein the first amino acid sequence comprises a heavy chain constant domain sequence, the second amino acid sequence comprises a heavy chain constant domain sequence, or both the first and the second amino acid sequence each comprises a heavy chain constant domain sequence.

13. A composition comprising: a first portion comprising the antibody of any preceding claim, and a second portion comprising a second antibody or antibody fragment.

14. The antibody of any of claims 1-12, wherein (a) one or more amino acid of the first amino acid sequence is an unnatural amino acid; (b) one or more amino acid of the second amino acid sequence is an unnatural amino acid; or (c) one or more amino acid of the first amino acid sequence is an unnatural amino acid, and one or more amino acid of the second amino acid

sequence is an unnatural amino acid.

15. The antibody of any of claims 1-10, comprising an unnatural amino acid located within: a light chain constant domain sequence of the first amino acid sequence, a heavy chain constant domain sequence of the second amino acid sequence, or the light chain constant domain sequence of the first amino acid sequence and the heavy chain constant domain sequence of the first amino acid sequence.

16. The antibody of claim 15, wherein the heavy chain constant domain sequence comprises: (a) an amino acid sequence selected from SEQ ID NOS: 86 and 98; or (b) an amino acid sequence selected from one or more of SEQ ID NOS: 99-109.

17. The antibody of claim 15 or claim 16, wherein the light chain constant domain sequence

comprises an amino acid selected from: SEQ ID NOS: 111 and 112; or (b) an amino acid sequence selected from one or more of SEQ ID NOS: 113-123.

18. The antibody of any of claims 14-17, wherein the unnatural amino acid is para- acetylphenylalanine.

19. A composition comprising the antibody of any preceding claim and a cell-targeting molecule. 20. A composition comprising a cell-targeting molecule connected to the antibody of any of claims 14-18 via the unnatural amino acid.

21. The composition of claim 20, wherein the cell-targeting molecule interacts with prostate-specific membrane antigen (PSMA) or folate receptor.

22. The composition of any of claims 19-21, comprising a compound of Formula (III):

wherein:

A1 is selected from the group consisting of an aryl, a 5- to 6-membered

heteroaryl, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

A2 is selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each R1 is independently selected from H, alkyl, and haloalkyl;

each R2, R21, R22, R23, and R24 is independently selected from H, halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, and heteroarylalkyl;

each R3 is independently selected from halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, heteroarylalkyl, -NO2, and NR1R1;

each G1 and G2 is independently selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each Z, Z1, Z2, and Z3 is independently selected from the group consisting of a bond, -O-, and -N(R1)-;

Z4 is selected from a bond, aryl, and a 5- to 6-membered heteroaryl;

k, k1, k2, k3, and k4 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

m1, m2, and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

p is 0, 1, 2, 3 or 4;

L4 is a bond directly attached to a modified amino acid, or a linker bound to a modified amino acid, wherein the modified amino acid is part of the antibody;

Q is selected from the group consisting of:



and a stereoisomer thereof.

23. An antibody comprising a first amino acid sequence comprising: (a) one or more of SEQ ID NOS: 54-56; and (b) SEQ ID NO: 86, SEQ ID NO: 98, or an amino acid sequence having an unnatural amino acid replacing one or more amino acid residues of SEQ ID NO: 86.

24. The antibody of claim 23, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 87, 92, 96, or 124.

25. The antibody of claim 23 or claim 24, further comprising a second amino acid sequence

comprising: (a) one or more of SEQ ID NOS: 51-53, (b) one or more of SEQ ID NOS: 97, 59, 74, 110, or (c) a combination of (a) and (b).

26. A composition comprising the antibody of any of claims 23-25 and a cell-targeting molecule. 27. The composition of claim 26, wherein the cell-targeting molecule interacts with prostate-specific membrane antigen (PSMA) or a folate receptor.

28. A composition comprising an antibody of any of claims 23-27, comprising a compound of

Formula (III):


Formula (III)

wherein:

A1 is selected from the group consisting of an aryl, a 5- to 6-membered

;

A2 is selected from the group consisting of a

bond, 1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

A4 is selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each R1 is independently selected from H, alkyl, and haloalkyl;

each R2, R21, R22, R23, and R24 is independently selected from H, halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, and heteroarylalkyl;

each R3 is independently selected from halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, heteroarylalkyl, -NO2, and NR1R1;

each G1 and G2 is independently selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each Z, Z1, Z2, and Z3 is independently selected from the group consisting of a bond, -O-, and -N(R1)-;

Z4 is selected from a bond, aryl, and a 5- to 6-membered heteroaryl;

k, k1, k2, k3, and k4 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

m1, m2, and m3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

L4 is a bond directly attached to a modified amino acid, or a linker bound to a modified amino acid, wherein the modified amino acid is part of the antibody;

Q is selected from the group consisting of:

29. An antibody comprising: (a) a first amino acid sequence comprising one or more of SEQ ID NOS: 54-56; and (b) an unnatural amino acid.

30. The antibody of claim 29, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 87, 92, 96, or 124.

31. The antibody of claim 29 or claim 30, wherein the first amino acid sequence comprises one or more of SEQ ID NOS: 99-108.

32. The antibody of any of claims 29-31, wherein the first amino acid sequence comprises SEQ ID 98.

33. The antibody of any of claims 29-32, wherein the first amino acid sequence comprises the

unnatural amino acid.

34. The antibody of any of claims 29-33, further comprising a second amino acid sequence comprising: (a) one or more of SEQ ID NOS: 51-53, (b) one or more of SEQ ID NOS: 97, 59, 74, or 110, or (c) a combination of (a) and (b).

35. A composition comprising the antibody of any of claims 29-34, and a cell-targeting molecule. 36. The composition of claim 35, wherein the cell-targeting molecule interacts with prostate-specific membrane antigen (PSMA) or a folate receptor.

37. A composition comprising an antibody of any of claims 29-36, comprising a compound of

Formula (III):


Formula (III)

wherein:


A1 is selected from the group consisting of an aryl, a 5- to 6-membered

heteroaryl, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;


A2 is selected from the group consisting of a

-S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

;


A4 is selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each R1 is independently selected from H, alkyl, and haloalkyl;

each R2, R21, R22, R23 and R24 is independently selected from H, halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, and heteroarylalkyl;

each R3 is independently selected from halo, -OR1, -CN, -SR1, alkyl, cycloalkyl, haloalkyl, arylalkyl, or heteroarylalkyl, -NO2, and NR1R1;

each G1 and G2 is independently selected from the group consisting of a

bond, -C(O)-, -N(R1)-, -O-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1,2N(R1)-, and -N(R1)S(O)1,2-;

each Z, Z1, Z2, and Z3 is independently selected from the group consisting of a bond, -O-, and -N(R1)-;

Z4 is selected from a bond, aryl, and a 5- to 6-membered heteroaryl;

k, k1, k2, k3, and k4 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

m1, m2 and m3 are each independentl selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

L4 is a bond directly attached to a modified amino acid, or a linker bound to a modified amino acid, wherein the modified amino acid is part of the antibody;

is selected from the group consisting of:

E is selected from the group consisting of:

, and a stereoisomer thereof.


. compos tion comprising: (a an am no ac sequence comprising one or more of SEQ ID NOS: 51-56 and an unnatural amino acid; and (b) a cell-targeting molecule linked to the amino acid sequence via the unnatural amino acid.

39. The composition of claim 38, wherein the unnatural amino acid is located within a heavy chain constant domain sequence of the amino acid sequence.

40. The composition of claim 38 or claim 39, wherein the amino acid sequence comprises one or more of SEQ ID NOS: 87, 92, 96, or 124.

41. The composition of any of claims 38-40, wherein the amino acid sequence comprises: one or more of SEQ ID NOS: 99-108.

42. The composition of any of claims 38-41, wherein the amino acid sequence comprises: SEQ ID NO: 86, SEQ ID NO: 98, or an amino acid sequence having the unnatural amino acid replace one or more amino acid residues of SEQ ID NO: 86.

43. The composition of any of claims 38-42, comprising a second amino acid sequence comprising:

(a) one or more of SEQ ID NOS: 51-53; (b) one or more of SEQ ID NOS: 97, 59, 74, 110; or (c) a combination of (a) and (b).

44. The composition of any of claims 38-43, wherein the unnatural amino acid is para- acetylphenylalanine.

45. The composition of any of claims 38-44, wherein the cell-targeting molecule interacts with

prostate-specific membrane antigen (PSMA) or folate receptor.