Antibody-Drug Conjugates and Related Compounds, Compositions, and Methods
Antibody-cytotoxin antibody-drug conjugates and related compounds, such as linker-cytotoxin conjugates and the linkers used to make them, tubulysin analogs, and intermediates in their synthesis; compositions; and methods, including methods of treating cancers.
1 . An antibody-drug conjugate of the formula:
A(-PD-L-CTX) n ,
where:
A is an antibody,
PD is pyrrole-2,5-dione or pyrrolidine-2,5-dione,
the double bond represents bonds from the 3- and 4-positions of the pyrrole-2,5-dione or pyrrolidine-2,5-dione to the two sulfur atoms of an opened cysteine-cysteine disulfide bond in the antibody,
L is —(CH 2 ) m — or —(CH 2 CH 2 O) m CH 2 CH 2 —,
CTX is a cytotoxin bonded to L by an amide bond,
n is an integer of 1 to 4, and
m is an integer of 1 to 12.
2 . The antibody-drug conjugate of claim 1 where A is a monoclonal antibody.
3 . The antibody-drug conjugate of claim 1 or 2 where A is a human or humanized antibody.
4 . The antibody-drug conjugate of any one of claims 1 to 3 where A is an antibody that is specific to a cancer antigen.
5 .- 12 . (canceled)
13 . A pharmaceutical composition comprising an antibody-drug conjugate of claim 1 .
14 . A method of treating a cancer by administering to a human suffering therefrom an effective amount of an antibody-drug conjugate of claim 1 .
15 . A linker-cytotoxin conjugate of formula A, B, or C:
where R is C 1-6 alkyl, optionally substituted with halo or hydroxyl; phenyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl; naphthyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl; or 2-pyridyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl,
L is —(CH 2 ) m — or —(CH 2 CH 2 O) m CH 2 CH 2 —,
CTX is a cytotoxin bonded to L by an amide bond, and
m is an integer of 1 to 12.
16 . The linker-cytotoxin conjugate of claim 15 where the conjugate is of formula A.
17 . The linker-cytotoxin conjugate of claim 15 where the conjugate is of formula B.
18 . The linker-cytotoxin conjugate of claim 15 where the conjugate is of formula C.
19 .- 24 . (canceled)
25 . A linker of formula AA, BB, or CC:
where R is C 1-6 alkyl, optionally substituted with halo or hydroxyl; phenyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl; naphthyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl; or 2-pyridyl, optionally substituted with halo, hydroxyl, carboxyl, C 1-3 alkoxycarbonyl, or C 1-3 alkyl,
L is —(CH 2 ) m — or —(CH 2 CH 2 O) m CH 2 CH 2 —,
Z is carboxyl, C 1-6 alkoxycarbonyl, or amino, and
m is an integer of 1 to 12.
26 . The linker of claim 25 where the linker is of formula AA.
27 . The linker of claim 25 where the linker is of formula BB.
28 . The linker of claim 25 where the linker is of formula CC.
29 . The linker of any one of claims 25 to 28 where R is 2-pyridyl.
30 .- 34 . (canceled)
35 . A linker of formula AAA, BBB, or CCC:
where R′ is chloro, bromo, iodo, C 1-6 alkylsulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, or 4-toluenesulfonyloxy,
L is —(CH 2 ) m — or —(CH 2 CH 2 O) m CH 2 CH 2 —,
Z is carboxyl, C 1-6 alkoxycarbonyl, or amino, and
m is an integer of 1 to 12.
36 . The linker of claim 35 where the linker is of formula AAA.
37 . The linker of claim 35 where the linker is of formula BBB.
38 . The linker of claim 35 where the linker is of formula CCC.
39 .- 47 . (canceled)