AURISTATIN-ANTIBODY CONJUGATES AND USES THEREOF

1 . An antibody drug conjugate comprising an auristatin linked to an antibody or fragment thereof through a phenyl group of the auristatin.

2 . The antibody drug conjugate of claim 1 , wherein the auristatin is of Formula (I):

wherein

each R 1 , R 2 , R 4 , R 6 , and R 12 is independently hydrogen or optionally substituted alkyl;

each R 3 , R 5 , R 7 , and R 11 is independently optionally substituted alkyl;

each R 8 and R 10 is independently optionally substituted alkyl;

each R 13 and R 14 are independently hydrogen, halogen, —CN, —OR a , —COOR a , —N(R a ) 2 , optionally substituted alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, or optionally substituted 5-, or 6-membered heteroaryl;

each R 9 is independently hydrogen, halogen, —OR a , —N(R a ) 2 , —SO 2 N(R a ) 2 , —CO 2 N(R a ) 2 , or optionally substituted alkyl; or 2 R 9 on the same carbon are taken together to form an oxo; or 2 R 9 on the adjacent carbons are taken together to form an alkene;

each R 15 is independently hydrogen, halogen, —OR a , —N(R a ) 2 , —SO 2 N(R a ) 2 , —CO 2 N(R a ) 2 , or optionally substituted alkyl;

each R a is hydrogen or optionally substituted alkyl;

n is 0-5; and

m is 0-3.

3 . The antibody drug conjugate of claim 2 , wherein:

R 2 is methyl;

R 3 is isopropyl;

R 4 is hydrogen;

R 5 is isopropyl;

R 6 is methyl;

R 7 is 2-butyl;

R 8 is methyl;

R 9 is hydrogen;

R 10 is methyl;

R 11 is methyl;

R 12 is hydrogen;

m is 0; and

n is 0.

4 . The antibody drug conjugate of claim 3 , wherein

R 1 is methyl; R 13 is methyl; and R 14 is —OH; or

R 1 is hydrogen; R 13 is methyl; and R 14 is —OH; or

R 1 is methyl; R 13 is —COOH; and R 14 is hydrogen; or

R 1 is hydrogen; R 13 is —COOH; and R 14 is hydrogen; or

R 1 is methyl; R 13 is 2-thiazolyl; and R 14 is hydrogen; or

R 1 is hydrogen; R 13 is 2-thiazolyl; and R 14 is hydrogen.

5 . The antibody drug conjugate of claim 1 , wherein the antibody or fragment thereof is linked through a primary amine on a phenyl group of an auristatin amine of Formula (II):

wherein

each R 1 , R 2 , R 4 , R 6 , and R 12 is independently hydrogen or optionally substituted alkyl;

each R 3 , R 5 , R 7 , and R 11 is independently optionally substituted alkyl;

each R 8 and R 10 is independently optionally substituted alkyl;

each R 13 and R 14 are independently hydrogen, halogen, —CN, —OR a , —COOR a , —N(R a ) 2 , optionally substituted alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 8 heterocycloalkyl, optionally substituted aryl, or optionally substituted 5-, or 6-membered heteroaryl;

each R 9 is independently hydrogen, halogen, —OR a , —N(R a ) 2 , —SO 2 N(R a ) 2 , —CO 2 N(R a ) 2 , or optionally substituted alkyl; or 2 R 9 on the same carbon are taken together to form an oxo; or 2 R 9 on the adjacent carbons are taken together to form an alkene;

each R 15 is independently hydrogen, halogen, —OR a , —N(R a ) 2 , —SO 2 N(R a ) 2 , —CO 2 N(R a ) 2 , or optionally substituted alkyl;

each R a is hydrogen or optionally substituted alkyl;

p is 0-4;

m is 0-3; and

X is a bond or C 1 -C 6 alkylene.

6 . The antibody drug conjugate of claim 1 , wherein the auristatin amine has the following structure:

7 . The antibody drug conjugate of claim 1 , wherein the antibody or fragment thereof binds an antigen on a cancer cell.

8 . The antibody drug conjugate of claim 1 , wherein the antibody or fragment thereof is an anti-CXCR4 antibody or fragment thereof.

9 . The antibody drug conjugate of claim 1 , wherein the phenyl group of the auristatin is linked to the antibody or fragment thereof via a linker.

10 . The antibody drug conjugate of claim 9 , wherein the linker comprises an amino acid.

11 . The antibody drug conjugate of claim 10 , wherein the amino acid is selected from a valine and a citrulline.

12 . The antibody drug conjugate of claim 9 , wherein the linker comprises a polyethylene glycol subunit.

13 . The antibody drug conjugate of claim 9 , wherein the auristatin and the linker together have a structure:

14 . A method of treating cancer or an autoimmune disease in a subject in need thereof, the method comprising administering an effective amount of the antibody drug conjugate of claim 1 to the subject.

15 . An antibody drug conjugate comprising a monomethyl auristatin linked to an antibody or fragment thereof through a non-cleavable linker.

16 . The antibody drug conjugate of claim 15 , wherein the non-cleavable linker links the antibody or fragment thereof to a terminal amino group of monomethyl auristatin E.

17 . The antibody drug conjugate of claim 15 , wherein the monomethyl auristatin E and the non-cleavable linker together have a structure:

18 . A method of treating cancer or an autoimmune disease in a subject in need thereof, the method comprising administering an effective amount of the antibody drug conjugate of claim 15 to the subject.

19 . A method of producing an antibody drug conjugate, the method comprising coupling an auristatin with a linker comprising an N-hydroxy-succinimide (NHS) ester.

20 . The method of claim 19 , wherein coupling the auristatin with the linker comprising the N-hydroxy-succinimide (NHS) ester produces a structure selected from: