ANTIBODY DRUG CONJUGATES FOR ABLATING HEMATOPOIETIC STEM CELLS
First Claim
Patent Images
1. A conjugate of Formula (I) or a pharmaceutically acceptable salt thereof;
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A-(LB-(D)n)y
Formula (I)wherein;
A is an antibody fragment that specifically binds to human cKIT;
LB is a linker;
D is a cytotoxic agent;
n is an integer from 1 to 10, andy is an integer from 1 to 10.
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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.
2 Citations
50 Claims
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1. A conjugate of Formula (I) or a pharmaceutically acceptable salt thereof;
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A-(LB-(D)n)y
Formula (I)wherein; A is an antibody fragment that specifically binds to human cKIT; LB is a linker; D is a cytotoxic agent; n is an integer from 1 to 10, and y is an integer from 1 to 10. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 18, 19, 20, 21, 22, 23, 24, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)
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- 10. A conjugate having the structure of Formula (C):
- 12. A conjugate having the structure of Formula (D):
- 14. A conjugate having the structure of Formula (E):
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16. A conjugate selected from:
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17. A conjugate selected from:
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46. An antibody or antibody fragment that specifically binds to human cKIT, wherein the antibody or antibody fragment is selected from any of the following:
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(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. - View Dependent Claims (47, 48, 49, 50)
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Specification