Anti-human CD45RC antibodies and uses thereof
Isolated anti-human CD45RC antibodies or binding fragments thereof, nucleic acids and expression vector encoding the same, compositions including the same, and uses thereof as medicaments, including for the prevention and/or treatment of CD45RC high -related diseases (including autoimmune diseases, undesired immune responses, monogenic diseases, and lymphoma or cancer), in particular for use in preventing and/or treating graft-versus-host disease (GVHD).
1. An isolated anti-human CD45RC antibody or binding fragment thereof, wherein said antibody or binding fragment thereof comprises:
(a) a heavy chain variable region (HCVR) which comprises the following three complementary-determining regions (CDRs):
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 100, 116, 117, 118 and 119; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a light chain variable region (LCVR) which comprises the following three CDRs:
(i) V L -CDR1 with a sequence selected from the group consisting of sequences SEQ ID NO: 15 (SASSSVS-X-YMH) and SEQ ID NO: 18 (RASSSVS-X-YMH), wherein X is absent or is selected from the group consisting of Asn (N), Ser(S) and Gly (G);
(ii) V L -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 16, 19, 20, 22, 111, 120 and 127; and
(iii) V L -CDR3 with a sequence selected from the group consisting of sequences SEQ ID NOs: 17 and 21.
2. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises a combination of 3 HCVR's CDRs and 3 LCVR's CDRs as set forth the table below:
CDRs'
V H -
V H -
V H -
V L -
V L -
V L -
combination #
CDR1
CDR2
CDR3
CDR1
CDR2
CDR3
#1
1
4
3
15
16
17
#2
1
4
3
18
16
17
#3
1
4
3
18
19
17
#4
1
4
3
18
20
17
#5
1
4
3
18
19
21
#6
1
4
3
18
22
17
#7
1
5
3
15
16
17
#8
1
5
3
18
16
17
#9
1
5
3
18
19
17
#10
1
5
3
18
20
17
#11
1
5
3
18
19
21
#12
1
5
3
18
22
17
#13
1
6
3
15
16
17
#14
1
6
3
18
16
17
#15
1
6
3
18
19
17
#16
1
6
3
18
20
17
#17
1
6
3
18
19
21
#18
1
6
3
18
22
17
#19
1
7
3
15
16
17
#20
1
7
3
18
16
17
#21
1
7
3
18
19
17
#22
1
7
3
18
20
17
#23
1
7
3
18
19
21
#24
1
7
3
18
22
17
#25
1
8
3
15
16
17
#26
1
8
3
18
16
17
#27
1
8
3
18
19
17
#28
1
8
3
18
20
17
#29
1
8
3
18
19
21
#30
1
8
3
18
22
17
#31
1
9
3
15
16
17
#32
1
9
3
18
16
17
#33
1
9
3
18
19
17
#34
1
9
3
18
20
17
#35
1
9
3
18
19
21
#36
1
9
3
18
22
17
#37
1
10
3
15
16
17
#38
1
10
3
18
16
17
#39
1
10
3
18
19
17
#40
1
10
3
18
20
17
#41
1
10
3
18
19
21
#42
1
10
3
18
22
17
#43
1
11
3
15
16
17
#44
1
11
3
18
16
17
#45
1
11
3
18
19
17
#46
1
11
3
18
20
17
#47
1
11
3
18
19
21
#48
1
11
3
18
22
17
#49
1
100
3
15
16
17
#50
1
100
3
18
16
17
#51
1
100
3
18
19
17
#52
1
100
3
18
20
17
#53
1
100
3
18
19
21
#54
1
100
3
18
22
17
#55
1
4
3
18
111
17
#56
1
5
3
18
111
17
#57
1
6
3
18
111
17
#58
1
7
3
18
111
17
#59
1
8
3
18
111
17
#60
1
9
3
18
111
17
#61
1
10
3
18
111
17
#62
1
11
3
18
111
17
#63
1
100
3
18
111
17
#64
1
116
3
15
16
17
#65
1
116
3
18
16
17
#66
1
116
3
18
19
17
#67
1
116
3
18
20
17
#68
1
116
3
18
19
21
#69
1
116
3
18
22
17
#70
1
116
3
18
111
17
#71
1
117
3
15
16
17
#72
1
117
3
18
16
17
#73
1
117
3
18
19
17
#74
1
117
3
18
20
17
#75
1
117
3
18
19
21
#76
1
117
3
18
22
17
#77
1
117
3
18
111
17
#78
1
118
3
15
16
17
#79
1
118
3
18
16
17
#80
1
118
3
18
19
17
#81
1
118
3
18
20
17
#82
1
118
3
18
19
21
#83
1
118
3
18
22
17
#84
1
118
3
18
111
17
#85
1
119
3
15
16
17
#86
1
119
3
18
16
17
#87
1
119
3
18
19
17
#88
1
119
3
18
20
17
#89
1
119
3
18
19
21
#90
1
119
3
18
22
17
#91
1
119
3
18
111
17
#92
1
4
3
15
120
17
#93
1
5
3
15
120
17
#94
1
6
3
15
120
17
#95
1
7
3
15
120
17
#96
1
8
3
15
120
17
#97
1
9
3
15
120
17
#98
1
10
3
15
120
17
#99
1
11
3
15
120
17
#100
1
100
3
15
120
17
#101
1
116
3
15
120
17
#102
1
117
3
15
120
17
#103
1
118
3
15
120
17
#104
1
119
3
15
120
17
#105
1
4
3
15
127
17
#106
1
5
3
15
127
17
#107
1
6
3
15
127
17
#108
1
7
3
15
127
17
#109
1
8
3
15
127
17
#110
1
9
3
15
127
17
#111
1
10
3
15
127
17
#112
1
11
3
15
127
17
#113
1
100
3
15
127
17
#114
1
116
3
15
127
17
#115
1
117
3
15
127
17
#116
1
118
3
15
127
17
#117
1
119
3
15
127
17.
3. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
(a) a HCVR which comprises the following three CDRs:
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 4 and 5; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a LCVR which comprises the following three CDRs:
(i) V L -CDR1 of sequence SEQ ID NO: 15, wherein X is absent;
(ii) V L -CDR2 of sequence SEQ ID NO: 16; and
(iii) V L -CDR3 of sequence SEQ ID NO: 17.
4. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
(a) a HCVR which comprises the following three CDRs:
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 of sequence SEQ ID NO: 4; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a LCVR which comprises the following three CDRs:
(i) V L -CDR1 of sequence SEQ ID NO: 15, wherein X is absent;
(ii) V L -CDR2 of sequence SEQ ID NO: 16; and
(iii) V L -CDR3 of sequence SEQ ID NO: 17.
5. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
(a) a HCVR which comprises the following three CDRs:
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 4, 6, and 100; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a LCVR which comprises the following three CDRs:
(i) V L -CDR1 with a sequence selected from the group consisting of sequences SEQ ID NOs: 15 and 18, wherein X is absent;
(ii) V L -CDR2 of sequence SEQ ID NO: 16; and
(iii) V L -CDR3 of sequence SEQ ID NO: 17.
6. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
1) a HCVR of sequence SEQ ID NO: 61 and a LCVR of sequence SEQ ID NO: 81;
2) a HCVR of sequence SEQ ID NO: 62 and a LCVR of sequence SEQ ID NO: 82;
3) a HCVR of sequence SEQ ID NO: 62 and a LCVR of sequence SEQ ID NO: 83;
4) a HCVR of sequence SEQ ID NO: 62 and a LCVR of sequence SEQ ID NO: 84;
5) a HCVR of sequence SEQ ID NO: 63 and a LCVR of sequence SEQ ID NO: 82;
6) a HCVR of sequence SEQ ID NO: 63 and a LCVR of sequence SEQ ID NO: 83;
7) a HCVR of sequence SEQ ID NO: 63 and a LCVR of sequence SEQ ID NO: 84;
8) a HCVR of sequence SEQ ID NO: 64 and a LCVR of sequence SEQ ID NO: 82;
9) a HCVR of sequence SEQ ID NO: 64 and a LCVR of sequence SEQ ID NO: 83;
10) a HCVR of sequence SEQ ID NO: 64 and a LCVR of sequence SEQ ID NO: 84;
11) a HCVR of sequence SEQ ID NO: 101 and a LCVR of sequence SEQ ID NO: 85;
12) a HCVR of sequence SEQ ID NO: 101 and a LCVR of sequence SEQ ID NO: 103;
13) a HCVR of sequence SEQ ID NO: 65 and a LCVR of sequence SEQ ID NO: 85;
14) a HCVR of sequence SEQ ID NO: 65 and a LCVR of sequence SEQ ID NO: 103;
15) a HCVR of sequence SEQ ID NO: 62 and a LCVR of sequence SEQ ID NO: 85;
16) a HCVR of sequence SEQ ID NO: 101 and a LCVR of sequence SEQ ID NO: 82;
17) a HCVR of sequence SEQ ID NO: 121 and a LCVR of sequence SEQ ID NO: 85;
18) a HCVR of sequence SEQ ID NO: 122 and a LCVR of sequence SEQ ID NO: 85;
19) a HCVR of sequence SEQ ID NO: 123 and a LCVR of sequence SEQ ID NO: 85;
20) a HCVR of sequence SEQ ID NO: 124 and a LCVR of sequence SEQ ID NO: 85;
21) a HCVR of sequence SEQ ID NO: 63 and a LCVR of sequence SEQ ID NO: 85;
22) a HCVR of sequence SEQ ID NO: 67 and a LCVR of sequence SEQ ID NO: 85;
23) a HCVR of sequence SEQ ID NO: 67 and a LCVR of sequence SEQ ID NO: 103; or
24) a HCVR of sequence SEQ ID NO: 61 and a LCVR of sequence SEQ ID NO: 113; or
25) a HCVR of sequence SEQ ID NO: 61 and a LCVR of sequence SEQ ID NO: 126; or
26) a HCVR and a LCVR comprising a sequence of the non-CDR regions sharing at least 70% of identity with the sequence of the non-CDR regions of the HCVR and LCVR according to 1) to 25).
7. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
(a) a HCVR which comprises the following three CDRs:
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11,100, 116, 117, 118 and 119; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a LCVR which comprises the following three CDRs:
(i) V L -CDR1 with a sequence selected from the group consisting of sequences SEQ ID NOs: 15 and 18, wherein X in SEQ ID NOs: 15 and 18 is selected from the group consisting of Asn (N), Ser(S) and Gly (G);
(ii) V L -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 16, 19, 20, 22, 111,120 and 127; and
(iii) V L -CDR3 with a sequence selected from the group consisting of sequences SEQ ID NOs: 17 and 21.
8. The isolated antibody or binding fragment thereof according to claim 7 , wherein the amino acid residue at Kabat position L71 of the LCVR is Phe (F).
9. A nucleic acid encoding the isolated antibody or binding fragment thereof according to claim 1 .
10. An expression vector comprising the nucleic acid according to claim 9 .
11. A cell comprising the nucleic acid according to claim 9 or an expression vector comprising the nucleic acid.
12. A pharmaceutical composition comprising the isolated antibody or binding fragment thereof according to claim 1 , a nucleic acid encoding the isolated antibody or binding fragment thereof, an expression vector comprising the nucleic acid, or a cell comprising the nucleic acid or the expression vector, and at least one pharmaceutically acceptable excipient.
13. A method of inducing immune tolerance in a subject in need thereof, comprising administering to said subject the isolated antibody or binding fragment thereof according to claim 1 , a nucleic acid encoding the isolated antibody or binding fragment thereof, an expression vector comprising the nucleic acid, or a cell comprising the nucleic acid or the expression vector.
14. A method of preventing and/or reducing transplant rejections in a subject in need thereof, comprising administering to said subject the isolated antibody or binding fragment thereof according to claim 1 , a nucleic acid encoding the isolated antibody or binding fragment thereof, an expression vector comprising the nucleic acid, or a cell comprising the nucleic acid or the expression vector.
15. A method of reducing and/or treating CD45RC high -related conditions in a subject in need thereof, comprising administering to said subject the isolated antibody or binding fragment thereof according to claim 1 , a nucleic acid encoding the isolated antibody or binding fragment thereof, an expression vector comprising the nucleic acid, or a cell comprising the nucleic acid or the expression vector.
16. The method of reducing and/or treating CD45RC high related conditions according to claim 15 , wherein the CD45RC high -related condition is selected from the group consisting of autoimmune diseases, undesired immune responses, monogenic diseases, lymphoma and cancer.
17. A method of preventing and/or treating graft-versus-host disease (GVHD) in a subject in need thereof, comprising administering to said subject the isolated antibody or binding fragment thereof according to claim 1 , a nucleic acid encoding the isolated antibody or binding fragment thereof, an expression vector comprising the nucleic acid, or a cell comprising the nucleic acid or the expression vector.
18. A method for detecting or quantifying hCD45RC in a sample, cell, tissue or organ, comprising contacting said sample, cell, tissue or organ with the isolated antibody or binding fragment thereof according to claim 1 .
19. The method for detecting or quantifying hCD45RC according to claim 18 , wherein the isolated antibody or binding fragment thereof is labelled.
20. The isolated antibody or binding fragment thereof according to claim 1 , wherein said antibody or binding fragment thereof comprises:
(a) a HCVR which comprises the following three CDRs:
(i) V H -CDR1 of sequence SEQ ID NO: 1;
(ii) V H -CDR2 with a sequence selected from the group consisting of sequences SEQ ID NOs: 4 and 118; and
(iii) V H -CDR3 of sequence SEQ ID NO: 3; and
(b) a LCVR which comprises the following three CDRs:
(i) V L -CDR1 of sequence SEQ ID NO: 15, wherein X is absent;
(ii) V L -CDR2 of sequence SEQ ID NO: 120; and
(iii) V L -CDR3 of sequence SEQ ID NO: 17.