IP Library › Granted Patent US 10,787,480
Granted Patent B2
US 10,787,480 · App. 16/439,204 · Granted Sep 29, 2020

Cytotoxic peptides and conjugates thereof

Inventors: Bernhard Hubert Geierstanger (Solana Beach, CA); Jan Grunewald (San Diego, CA); Yunho Jin (San Diego, CA); Weijia Ou (San Diego, CA); Tetsuo Uno (San Diego, CA); Yongqin Wan (San Diego, CA); Xing Wang (San Diego, CA)
Assignee: Novartis AG
C07K5/0205A61K47/6817A61K47/6851C07K7/02C07K16/32
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Quick Facts
Patent No.
US 10,787,480
App. No.
16/439,204
Granted
Sep 29, 2020
Kind
B2
Abstract

Disclosed herein are novel cytotoxic peptides of formula (I) as described herein: and the use of such peptides in making immunoconjugates (i.e Antibody Drug Conjugates) Also described herein are immunoconjugates (i.e Antibody Drug Conjugates) comprising such novel cytotoxic peptide linked to an antigen binding moiety, such as an antibody; where such immunoconjugates are useful for treating cell proliferative disorders. The invention further provides pharmaceutical compositions comprising these immunoconjugates, compositions comprising the immunoconjugates with a therapeutic co-agent, and methods to use these immunoconjugates and compositions for treating cell proliferation disorders.

Claims (78)

1. An immunoconjugate of Formula (II):

wherein:

Ab represents an antigen binding moiety comprising:

a) a heavy chain constant region that comprises a heavy chain constant region of SEQ ID NO: 4 or 5, and a light chain constant region that comprises a light chain constant region of SEQ ID NO: 7;

b) a heavy chain constant region that comprises a heavy chain constant region of SEQ ID NO: 6, and a light chain constant region that comprises a light chain constant region of SEQ ID NO: 7;

or

c) a heavy chain constant region that comprises a heavy chain constant region of SEQ ID NO:10, and a light chain constant region that comprises a light chain constant region of SEQ ID NO:11;

L is -L 1 L 2 L 3 L 4 L 5 L 6 -, -L 6 L 5 L 4 L 3 L 2 L 1 -, -L 1 L 2 L 3 L 4 L 5 -, -L 5 L 4 L 3 L 2 L 1 -, -L 1 L 2 L 3 L 4 -, -L 4 L 3 L 2 L 1 -, -L 1 L 2 L 3 -, -L 3 L 2 L 1 -, -L 1 L 2 -, -L 2 L 1 - or -L 1 -,

wherein

L 1 is —(CH 2 ) m —, —C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O) (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)X 1 X 2 (CH 2 ) m NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —C(═O)X 1 X 2 C(═O)(CH 2 ) m NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m S(═O) 2 ((CH 2 ) m O) n (CH 2 ) m —, —C(═O)(CH 2 ) m NR 12 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)NH(CH 2 ) m NR 12 C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —C(═O)X 1 C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)X 1 C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —,

 —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)—, —(CH 2 ) m C(═O)X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)X 2 X 1 C(═O)—, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —(CH 2 ) m (O(CH 2 ) m ) n S(═O) 2 (CH 2 ) m —, —(CH 2 ) m NR 12 (CH 2 ) m C(═O)—, —(CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m C(O)X 2 X 1 C(═O)NR 12 (CH 2 ) m NHC(═O)—, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)X 1— , —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—,

 —((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n —, —(CH 2 ) m (O(CH 2 ) m ) n X 3 (CH 2 ) m —, —(CH 2 ) m X 3 ((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)(CH 2 ) m NR 12 C(═O)O(CH 2 ) m —, —(CH 2 ) m OC(═O)NR 12 (CH 2 ) m C(═O)—, —S(═O) 2 (CH 2 ) m NR 12 C(═O)O(CH 2 ) m —, —(CH 2 ) m OC(═O)NR 12 (CH 2 ) m S(═O) 2 —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m S(CH 2 ) m —, —NR 12 C(═O)(CH 2 ) m —, —NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 —, —(CH 2 ) m C(═O)NR 12 —, —(CH 2 ) m NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m —, —((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n —, —NR 12 (CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m —, —(CH 2 ) m C(R 12 ) 2 NR 12 —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 —, —NR 12 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 C(R 12 ) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 (CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —NR 12 (CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —NR 12 (CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —NR 12 C(R 12 ) 2 (CH 2 ) m OC(═O)NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 C(═O)O(CH 2 ) m C(R 12 ) 2 NR 12 —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 , —NR 12 ((CH 2 ) m O) n (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(CH 2 ) m NR 12 , —NR 12 ((CH 2 ) m O) n (CH 2 ) m —, —NR 12 ((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(CH 2 ) m (O(CH 2 ) m ) n NR 12 —, —(C(R 12 ) 2 ) m —, —(CH 2 CH 2 O) n —, —(OCH 2 CH 2 ) n —, —(CH 2 ) m O(CH 2 ) m —, —S(═O) 2 (CH 2 ) m —, —(CH 2 ) m S(═O) 2 —S(═O) 2 (CH 2 ) m NR 12 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NR 12 (CH 2 ) m S(═O) 2 —, —S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m S(═O) 2 —, —(CH 2 ) m X 2 X 1 C(═O)—, —C(═O)X 1 X 2 (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)X 2 X 1 C(═O)—, —C(═O)X 1 X 2 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m X 2 X 1 C(═O)—, —C(═O)X 1 X 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m NR 12 C(═O)—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m C(═O)—, —C(═O)(CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NR 12 (CH 2 ) m (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n (CH 2 ) m NR 12 C(═O)(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)X 1 X 2 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)X 2 X 1 C(═O)NR 12 (CH 2 ) m —, —X 4 X 1 X 2 C(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)X 2 X 1 X 4 —, —X 1 C(═O)(CH 2 ) m NHC(═O)(CH 2 ) m —, —(CH 2 ) m C(═O)NH(CH 2 ) m C(═O)X 1 —, —C(═O)CHR aa NR 12 —, —CHR aa C(═O)—, —C(═O)NR 12 —, —C(═O)O—, —S—, —SCH 2 (C═O)NR 12 —, —NR 12 C(═O)CH 2 S—, —S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 —, —(CH 2 ) 2 S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 CH 2 CH 2 —, —NR 12 C(═S), —(CH 2 ) m X 3 (O(CH 2 ) m ) n C(═O)—, —C(═O)((CH 2 ) m O) n X 3 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)((CH 2 ) m O) n (CH 2 ) m —, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m NR 12 C(═O)NR 12 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m NR 12 C(═O), —C(═O)NR 12 (CH 2 ) m X 3 (CH 2 ) m —, —NR 12 S(═O) 2 (CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m S(═O) 2 NR 12 —,

R 20 is H or Me, and R 30 is H, —CH 3 or phenyl;

R 21 is

each R 25 is independently H or C 1-4 alkyl;

R aa is a side chain of an amino acid selected from glycine, alanine, tryptophan, tyrosine, phenylalanine, leucine, isoleucine, valine, asparagine, glutamic acid, glutamine, aspatic acid, histidine, arginine, lysine, cysteine, methionine, serine, threonine, phenylglycine and t-butylglycine;

R 32 is independently selected from H, C 1-4 alkyl, phenyl, pyrimidine or pyridine;

R 33 is independently selected from

R 34 is independently H, C 1-4 alkyl, or C 1-6 haloalkyl;

X 1 is

X 2 is

X 3 is

 and

X 4 is

and L 2 , L 3 , L 4 , L 5 , and L 6 are each independently a bond or L 1 ;

y is an integer from 1 to 16;

R 101 is a 6 membered heterocycloalkyl divalent radical containing 1-2 N heteroatoms and a C 1 -C 2 alkylene bridge, wherein the 6 membered heterocycloalkyl divalent radical is C-linked to the

 group and is N-linked to L 1 or is C-linked to L 1 , and the 6 membered heterocycloalkyl divalent radical is unsubstituted or substituted with 1 to 3 substituents independently selected from R 5 and R 6 ;

or R 101 is a 5-8 membered fused bicyclic heterocycloalkyl divalent radical containing 1-2 N heteroatoms, wherein the 5-8 membered fused bicyclic heterocycloalkyl divalent radical is C-linked to the

 group and is N-linked to L 1 or is C-linked to L 1 , and the 5-8 membered fused bicyclic heterocycloalkyl divalent radical is unsubstituted or substituted with 1 to 3 substituents independently selected from R 5 and R 6 ;

R 2 is —C 1 -C 6 alkyl;

R 3 is

R 4 is —OH, C 1 -C 6 alkoxy, —N(R 14 ) 2 , —R 16 , —NR 12 (CH 2 ) m N(R 14 ) 2 , or —NR 12 (CH 2 ) m R 16 , —NHS(O) 2 R 11 or

R 5 is C 1 -C 6 alkyl, —C(═O)R 11 , —(CH 2 ) m OH, —C(═O)(CH 2 ) m OH, —C(═O)((CH 2 ) m O) n R 12 , —((CH 2 ) m O) n R 12 , or C 1 -C 6 alkyl which is optionally substituted with —CN, —C(═O)NH 2 or 1 to 5 hydroxyl,

R 6 is halo, oxo, OH, C 1 -C 6 alkyl, —N(R 14 ) 2 , —R 16 or —NR 12 C(═O)R 11 ;

R 11 is C 1 -C 6 alkyl or C 1 -C 6 alkyl which is optionally substituted with 1 to 5 hydroxyl;

each R 12 is independently selected from H and C 1 -C 6 alkyl;

R 13 is tetrazolyl, imidazolyl substituted with phenyl, oxadiazolyl substituted with phenyl, pyrazolyl, pyrimidinyl,

 or —CH 2 S(═O) 2 NH 2 ;

each R 14 is independently H or C 1 -C 6 alkyl;

R 16 is an N-linked 4-8 membered heterocycloalkyl containing 1-2 heteroatoms independently selected from N and O;

R 19 is H or C 1 -C 6 alkyl;

each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

and

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18.

2. The immunoconjugate of claim 1 , wherein the immunoconjugate of Formula (II) is an immunoconjugate having the structure of Formula (IIb) or Formula (IIc):

3. The immunoconjugate of claim 1 , wherein R 101 is

4. The immunoconjugate of claim 3 , wherein R 3 is

and R 19 is H.

5. The immunoconjugate of claim 4 , wherein:

R 4 is —OH, C 1 -C 6 alkoxy, —N(R 14 ) 2 , —R 16 , —NR 12 (CH 2 ) m N(R 14 ) 2 , or —NR 12 (CH 2 ) m R 16 .

6. The immunoconjugate of claim 5 , wherein R 2 is methyl, ethyl, isopropyl or sec-butyl.

7. The immunoconjugate of claim 6 , wherein:

L 1 is —(CH 2 ) m NHC(═O)(CH 2 ) m X 3 (CH 2 ) m *—, —(CH 2 ) m C(═O)*—, —(CH 2 ) m —, —(CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m X 2 X 1 C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n S(═O) 2 (CH 2 ) m *—, —(CH 2 ) m NH(CH 2 ) m C(═O)*—, —((CH 2 ) m O) n (CH 2 ) m *—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m X 2 X 1 C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n X 2 X 1 C(═O)*—, —(CH 2 ) m NHC(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m X 3 ((CH 2 ) m O) n (CH 2 ) m *—, —(CH 2 ) m C(═O)NH(CH 2 ) m *—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NH(CH 2 ) m *—, —(CH 2 ) m C(═O)NH(CH 2 ) m NHC(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m NHC(═O)*—, —(CH 2 ) m C(═O)NH(CH 2 ) m C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NH(CH 2 ) m NHC(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NH(CH 2 ) m C(═O)*—, —(CH 2 ) m C(═O)NH(CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NH(CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m C(═O)NH(CH 2 ) m NHC(═O)(CH 2 ) m *—, —(CH 2 ) m C(═O)NH(CH 2 ) m C(═O)NH(CH 2 ) m *—, —(CH 2 ) m X 3 (CH 2 ) m C(═O)NH(CH 2 ) m *—, —(CH 2 ) m S(═O) 2 *—, —(CH 2 ) m X 3 (CH 2 ) m S(═O) 2 *—, —(CH 2 ) m OC(═O)NH(CH 2 ) m C(═O)*—, or —(CH 2 ) m OC(═O)NH(CH 2 ) m S(═O) 2 *—, and wherein the * indicates the point of attachment to R 101 ;

L 2 is a bond,

 —S—, —SCH 2 (C═O)NH—, —NHC(═O)CH 2 S—, —SCH 2 CH 2 C(═O)NH—, —NHC(═O)CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 —, —S(═O) 2 CH 2 CH 2 S—, —SCH 2 CH 2 S(═O) 2 NH— or —NHS(═O) 2 CH 2 CH 2 S—, wherein the * indicates the point of attachment to L 1 , and

L 3 , L 4 , L 5 and L 6 are a bond.

8. The immunoconjugate of claim 7 , wherein:

L 1 is —(CH 2 ) m C(═O)*—, —(CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)*—, —(CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n S(═O) 2 (CH 2 ) m *— or (CH 2 ) m NR 12 (CH 2 ) m C(═O)*—, wherein the * indicates the point of attachment to R 101 ;

and

L 2 is

wherein the * indicates the point of attachment to L 1 ,

and L 3 , L 4 , L 5 and L 6 are a bond.

9. The immunoconjugate of claim 1 , wherein:

R 101 is

R 2 is methyl, ethyl, isopropyl or sec-butyl;

L is L 1 L 2 , wherein:

L 1 is —(CH 2 ) m C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)*—, —(CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m —, —(CH 2 ) m X 3 (CH 2 ) m C(═O)X 2 X 1 C(═O)*—, —(CH 2 ) m X 3 (CH 2 ) m (O(CH 2 ) m ) n C(═O)*—, —(CH 2 ) m (O(CH 2 ) m ) n S(═O) 2 (CH 2 ) m *— or —(CH 2 ) m NR 12 (CH 2 ) m C(═O)*—, wherein the * of L 1 indicates the point of attachment to R 101 ;

and

L 2 is

 wherein the * of L 2 indicates the point of attachment to L 1 ;

R 3 is

R 4 is —OH;

each m is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18, and

y is 1, 2, 3 or 4.

10. A pharmaceutical composition comprising an immunoconjugate of claim 1 , and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical composition comprising an immunoconjugate of claim 9 , and one or more pharmaceutically acceptable carriers.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 29, 2019
From: NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC. DBA THE GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION
To: IRM LLC
Reel/Frame 050208/0125 →
MERGER Recorded Aug 29, 2019
From: IRM, LLC
To: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD.
Reel/Frame 050208/0198 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 29, 2019
From: NOVARTIS INTERNATIONAL PHARMACEUTICAL LTD.
To: NOVARTIS INTERNATIONAL PHARMACEUTICAL AG
Reel/Frame 050209/0935 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 29, 2019
From: NOVARTIS INTERNATIONAL PHARMACEUTICAL AG
To: NOVARTIS AG
Reel/Frame 050209/0961 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2019
From: GEIERSTANGER, BERNHARD HUBERT; GRUNEWALD, JAN; OU, WEIJIA; UNO, TETSUO; WAN, YONGQIN; WANG, XING; JIN, YUNHO
To: NOVARTIS INSTITUTE FOR FUNCTIONAL GENOMICS, INC. DBA THE GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION
Reel/Frame 050203/0650 →
Continuity (4)
Continuation 15961531 · Apr 24, 2018
Continuation 15104727
Provisional Application 61917293 · Dec 17, 2013
Related Publication 20190382441A1 · Dec 19, 2019