US 2021/0228731 A1Published application

Antibody drug conjugates for ablating hematopoietic stem cells

AssigneeNovartis AG

InventorsAnthony Edward BOITANO, Matthew T. BURGER, Susan E. CELLITTI, Michael Paul COOKE, Catrin FINNER, Bernhard Hubert GEIERSTANGER, Si-Tuen LEE-HOEFLICH, HongNgoc Thi PHAM, Siew Ho SCHLEYER, Kathrin TISSOT, Tetsuo UNO, Yongqin WAN, Ben WEN, Qiang ZHANG

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Abstract

The present invention provides antibody drug conjugates, wherein an antibody or antibody fragment that specifically binds to human cKIT is linked to a drug moiety, optionally through a linker. The present invention further provides pharmaceutical compositions comprising the antibody drug conjugates; and methods of making and using such pharmaceutical compositions for ablating hematopoietic stem cells in a patient in need thereof.

Claims41

Dependent claims

A conjugate of Formula (I) or a pharmaceutically acceptable salt thereof;

A-(LB-(D)n)y Formula (I)
wherein:
A is an antibody fragment that specifically binds to human cKIT;
LB is a linker;
n is an integer from 1 to 10;
y is an integer from 1 to 10, and
D is a cytotoxic agent selected from a compound of Formula (A):
wherein:
R1 is
R2 is H, C1-C6alkyl, —C(═O)R3, —(CH2)mOH, —C(═O)(CH2)mOH, —C(═O)((CH2)mO)nR4, —((CH2)mO)nR4 or C1-C6alkyl which is optionally substituted with —CN, —C(═O)NH2 or 1 to 5 hydroxyl;
each R3 is independently selected from C1-C8alkyl and C1-C8alkyl which is optionally substituted with 1 to 5 hydroxyl;
and
each R4 is independently selected from H and C1-C6alkyl;
or D is a cytotoxic agent selected from a compound of Formula (B):
wherein:
R1 is
R2 is H, C1-C6alkyl, —C(═O)R3, —(CH2)mOH, —C(═O)(CH2)mOH, —C(═O)((CH2)mO)nR4, —((CH2)mO)nR4 or C1-C6alkyl which is optionally substituted with —CN, —C(═O)NH2 or 1 to 5 hydroxyl;
each R3 is independently selected from C1-C6alkyl and C1-C6alkyl which is optionally substituted with 1 to 5 hydroxyl;
and
each R4 is independently selected from H and C1-C6alkyl.

17 more elements

A conjugate having the structure of Formula (E):

wherein:
A represents an antibody fragment (e.g., Fab or Fab′) that specifically binds to human cKIT;
y is an integer from 1 to 10;
R2 is H, C1-C6alkyl, —C(═O)R3, —(CH2)mOH, —C(═O)(CH2)mOH, —C(═O)((CH2)mO)nR4, —((CH2)mO)nR4 or C1-C6alkyl which is optionally substituted with —CN, —C(═O)NH2 or 1 to 5 hydroxy;
each R3 is independently selected from C1-C6alkyl and C1-C6alkyl which is optionally substituted with 1 to 5 hydroxyl;
each R4 is independently selected from H and C1-C6alkyl;
L1 is —X1C(═O)((CH2)mO)p(CH2)m—**, —X1C(═O)(CH2)m—**, —X2X1C(═O)((CH2)mO)p(CH2)m—**, —X2X1C(═O)(CH2)m—**, —X3C(═O)((CH2)mO)p(CH2)m—**, —X3C(═O)(CH2)m—**, —X3C(═O)(CH2)mNHC(═O)((CH2)mO)p(CH2)m—**, —X3C(═O)(CH2)mNHC(═O)(CH2)m—**, —X3C(═O)(CH2)m—**, —X1C(═O)((CH2)mO)p(CH2)mX4(CH2)m—**, —X1C(═O)(CH2)mX4(CH2)m—**, —X2X1C(═O)((CH2)mO)p(CH2)mX4(CH2)m—** or —X2X1C(═O)(CH2)mX4(CH2)m—**, where ** indicates the point of attachment to R114;
X1 is
where ** indicates the point of attachment to the —NH— or to X2;
X2 is
where ** indicates the point of attachment to the —NH—;
X3 is
where ** indicates the point of attachment to the —NH—;
X4 is
where the * indicates the point of attachment is toward R114;
R114 is
—NR6C(═O)CH2—*, —NHC(═O)CH2—*, —S(═O)2CH2CH2—*, —(CH2)2S(═O)2CH2CH2—*, —NR6S(═O)2CH2CH2*, —NR6C(═O)CH2CH2*, —NH—, —C(═O)—, —NHC(═O)—*, —CH2NHCH2CH2—*, —NHCH2CH2—*, —S—,
where the * indicates the point of attachment to A;
each R6 is independently selected from H and C1-C6alkyl;
each R10 is independently selected from H, C1-C6alkyl, F, Cl, and —OH;
each R11 is independently selected from H, C1-C6alkyl, F, Cl, —NH2, —OCH3, —OCH2CH3, —N(CH3)2, —CN, —NO2 and —OH;
each R12 is independently selected from H, C16alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C14alkoxy substituted with —C(═O)OH and C14alkyl substituted with —C(═O)OH;
each R15 is independently selected from H, —CH3 and phenyl;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

22 more elements

A conjugate having the structure of Formula (G):

wherein:
A represents an antibody fragment (e.g., Fab or Fab′) that specifically binds to human cKIT;
y is an integer from 1 to 10;
R2 is H, C1-C6alkyl, —C(═O)R3, (CH2)mOH, —C(═O)(CH)mOH, —C(═O)((CH2)mO)nR4, —((CH2)mO)nR4 or C1-C6alkyl which is optionally substituted with —CN, —C(═O)NH2 or 1 to 5 hydroxy;
each R3 is independently selected from C1-C6alkyl and C1-C6alkyl which is optionally substituted with 1 to 5 hydroxyl;
each R4 is independently selected from H and C1-C6alkyl;
L1 is —X1C(═O)((CH2)mO)p(CH2)m—**, —X1C(═O)(CH2)m—**, —X2X1C(═O)((CH2)mO)p(CH2)m—**, —X2X1C(═O)(CH2)m—**, —X3C(═O)((CH2)mO)p(CH2)m—**, —X3C(═O)(CH2)m—**, —X3C(═O)(CH2)mNHC(═O)((CH2)mO)p(CH2)m—**, —X3C(═O)(CH2)mNHC(═O)(CH2)m—**, —X3C(═O)(CH2)m—**, —X1C(═O)((CH2)mO)p(CH2)mX4(CH2)m—**, —X1C(═O)(CH2)mX4(CH2)m—**, —X2X1C(═O)((CH2)mO)p(CH2)mX4(CH2)m—** or —X2X1C(═O)(CH2)mX4(CH2)m—**, where ** indicates the point of attachment to R4;
X1 is
where ** indicates the point of attachment to the —NH— or to X2;
X2 is
where ** indicates the point of attachment to the —NH—;
X3 is
where ** indicates the point of attachment to the —NH—;
X4 is
where the * indicates the point of attachment is toward R114;
R114 is
—NR6C(═O)CH2—*, —NHC(═O)CH2—*, —S(═O)2CH2CH2—*, —(CH2)2S(═O)2CH2CH2—*, —NR6S(═O)2CH2CH2—*, —NR6C(═O)CH2CH2—*, —NH—, —C(═O)—, —NHC(═O)—*, —CH2NHCH2CH2—*, —NHCH2CH2—*, —S—,
where the * indicates the point of attachment to A;
each R6 is independently selected from H and C1-C6alkyl;
each R10 is independently selected from H, C1-C6alkyl, F, Cl, and —OH;
each R11 is independently selected from H, C1-C6alkyl, F, Cl, —NH2, —OCH3, —OCH2CH3, —N(CH3)2, —CN, —NO2 and —OH;
each R12 is independently selected from H, C1-6alkyl, fluoro, benzyloxy substituted with —C(═O)OH, benzyl substituted with —C(═O)OH, C1-4alkoxy substituted with —C(═O)OH and C14alkyl substituted with —C(═O)OH;
each R15 is independently selected from H, —CH3 and phenyl;
each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, and
each p is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

22 more elements

An antibody or antibody fragment that specifically binds to human cKIT, wherein the antibody or antibody fragment is selected from any of the following:

(1) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 (Heavy Chain Complementarity Determining Region 1) of SEQ ID NO:
1, (b) a HCDR2 (Heavy Chain Complementarity Determining Region 2) of SEQ ID NO:
2, and (c) a HCDR3 (Heavy Chain Complementarity Determining Region 3) of SEQ ID NO:
3;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 (Light Chain Complementarity Determining Region 1) of SEQ ID NO:
16, (e) a LCDR2 (Light Chain Complementarity Determining Region 2) of SEQ ID NO:
17, and (f) a LCDR3 (Light Chain Complementarity Determining Region 3) of SEQ ID NO:
18;
(2) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
4, (b) a HCDR2 of SEQ ID NO:
5, (c) a HCDR3 of SEQ ID NO:
3;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
19, (e) a LCDR2 of SEQ ID NO:
20, and (f) a LCDR3 of SEQ ID NO:
21;
(3) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
6, (b) a HCDR2 of SEQ ID NO:
2, (c) a HCDR3 of SEQ ID NO:
3;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
16, (e) a LCDR2 of SEQ ID NO:
17, and (f) a LCDR3 of SEQ ID NO:
18;
(4) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
7, (b) a HCDR2 of SEQ ID NO:
8, (c) a HCDR3 of SEQ ID NO:
9;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
22, (e) a LCDR2 of SEQ ID NO:
20, and (f) a LCDR3 of SEQ ID NO:
18;
(5) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
27, (b) a HCDR2 of SEQ ID NO:
28, (c) a HCDR3 of SEQ ID NO:
29;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
42, (e) a LCDR2 of SEQ ID NO:
17, and (f) a LCDR3 of SEQ ID NO:
43;
(6) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
30, (b) a HCDR2 of SEQ ID NO:
31, (c) a HCDR3 of SEQ ID NO:
29;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
44, (e) a LCDR2 of SEQ ID NO:
20, and (f) a LCDR3 of SEQ ID NO:
45;
(7) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
32, (b) a HCDR2 of SEQ ID NO:
28, (c) a HCDR3 of SEQ ID NO:
29;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
42, (e) a LCDR2 of SEQ ID NO:
17, and (f) a LCDR3 of SEQ ID NO:
43;
(8) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
33, (b) a HCDR2 of SEQ ID NO:
34, (c) a HCDR3 of SEQ ID NO:
35;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
46, (e) a LCDR2 of SEQ ID NO:
20, and (f) a LCDR3 of SEQ ID NO:
43;
(9) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
60, (b) a HCDR2 of SEQ ID NO:
61, (c) a HCDR3 of SEQ ID NO:
62;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
75, (e) a LCDR2 of SEQ ID NO:
76, and (f) a LCDR3 of SEQ ID NO:
77;
(10) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
63, (b) a HCDR2 of SEQ ID NO:
64, (c) a HCDR3 of SEQ ID NO:
62;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
78, (e) a LCDR2 of SEQ ID NO:
79, and (f) a LCDR3 of SEQ ID NO:
80;
(11) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
65, (b) a HCDR2 of SEQ ID NO:
61, (c) a HCDR3 of SEQ ID NO:
62;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
75, (e) a LCDR2 of SEQ ID NO:
76, and (f) a LCDR3 of SEQ ID NO:
77;
(12) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
66, (b) a HCDR2 of SEQ ID NO:
67, (c) a HCDR3 of SEQ ID NO:
68;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
81, (e) a LCDR2 of SEQ ID NO:
79, and (f) a LCDR3 of SEQ ID NO:
77;
(13) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
86, (b) a HCDR2 of SEQ ID NO:
87, (c) a HCDR3 of SEQ ID NO:
88;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
101, (e) a LCDR2 of SEQ ID NO:
102, and (f) a LCDR3 of SEQ ID NO:
103;
(14) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
89, (b) a HCDR2 of SEQ ID NO:
90, (c) a HCDR3 of SEQ ID NO:
88;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
104, (e) a LCDR2 of SEQ ID NO:
105, and (f) a LCDR3 of SEQ ID NO:
106;
(15) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
91, (b) a HCDR2 of SEQ ID NO:
87, (c) a HCDR3 of SEQ ID NO:
88;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
101, (e) a LCDR2 of SEQ ID NO:
102, and (f) a LCDR3 of SEQ ID NO:
103;
(16) an antibody or antibody fragment comprising (i) a heavy chain variable region that comprises (a) a HCDR1 of SEQ ID NO:
92, (b) a HCDR2 of SEQ ID NO:
93, (c) a HCDR3 of SEQ ID NO:
94;
and (ii) a light chain variable region that comprises:
(d) a LCDR1 of SEQ ID NO:
107, (e) a LCDR2 of SEQ ID NO:
105, and (f) a LCDR3 of SEQ ID NO:
103;
(17) an antibody or antibody fragment comprising a heavy chain variable region (VH) that comprises SEQ ID NO:
10, and a light chain variable region (VL) that comprises SEQ ID NO:
23;
(18) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO:
36, and a VL that comprises SEQ ID NO:
47;
(19) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO:
69, and a VL that comprises SEQ ID NO:
82;
(20) an antibody or antibody fragment comprising a VH that comprises SEQ ID NO:
95, and a VL that comprises SEQ ID NO:
108;
(21) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO:
14, and a light chain that comprises SEQ ID NO:
25;
(22) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO:
40, and a light chain that comprises SEQ ID NO:
49;
(23) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO:
73, and a light chain that comprises SEQ ID NO:
84;
(24) an antibody or antibody fragment comprising a heavy chain that that comprises SEQ ID NO:
99, and a light chain that comprises SEQ ID NO:
110;
(25) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
118, and a light chain that comprises SEQ ID NO:
122;
(26) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
118, and a light chain that comprises SEQ ID NO:
123;
(27) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
124, and a light chain that comprises SEQ ID NO:
128;
(28) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
124, and a light chain that comprises SEQ ID NO:
129;
(29) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
130, and a light chain that comprises SEQ ID NO:
134;
(30) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
130, and a light chain that comprises SEQ ID NO:
135;
(31) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
136, and a light chain that comprises SEQ ID NO:
140;
(32) an antibody or antibody fragment comprising a heavy chain that comprises SEQ ID NO:
141, and a light chain that comprises SEQ ID NO:
145;
(33) an antibody comprising a heavy chain that that comprises SEQ ID NO:
12, and a light chain that comprises SEQ ID NO:
25;
(34) an antibody comprising a heavy chain that that comprises SEQ ID NO:
38, and a light chain that comprises SEQ ID NO:
49;
(35) an antibody comprising a heavy chain that that comprises SEQ ID NO:
71, and a light chain that comprises SEQ ID NO:
84;
or
(36) an antibody comprising a heavy chain that that comprises SEQ ID NO:
97, and a light chain that comprises SEQ ID NO:
110.

202 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/253,584Filed 19 Jun 2019
Priority: 20 Jun 2018
Published: 29 Jul 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

A61K 47/6849
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a receptor, a cell…
A61K 38/07
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: tetrapeptides
A61K 47/68031
Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates: the drug being an auristatin
A61K 47/6867
The antibody targeting a determinant of a tumour cell: the tumour determinant being from a cell of a blood cancer