Senescent cell-associated antigen-binding domains, antibodies and chimeric antigen receptors comprising the same, and uses thereof
The invention relates to DPP4-binding domains, as well as antibodies and chimeric antigen receptors (CAR) comprising the same. Also disclosed are methods for treating, preventing or alleviating senescence-related diseases or disorders, or for depleting and/or killing senescent cells.
1. A DPP4-binding domain, comprising a combination of three heavy chain variable region (HCVR)'s complementary-determining regions (CDRs) and three light chain variable region (LCVR)'s CDRs, said combination being as defined in any row of the table below, wherein the CDRs are defined by their SEQ ID NO:
V H -
V H -
V H -
V L -
V L -
V L -
Clone’s name
CDR1
CDR2
CDR3
CDR1
CDR2
CDR3
5826-13-R3A-A10
107
119
137
146
157
170
5826-13-R3A-B1
108
120
138
147
158
171
5826-13-R3A-B3
108
121
138
147
159
171
5826-13-R3A-D5
109
122
139
148
160
172
5826-13-R3A-D6
108
123
138
149
159
171
5826-13-R4A-E2
108
124
138
147
159
171
5826-13-R4A-E6
110
125
140
146
161
170
5826-13-R4A-E9
108
126
141
149
159
171
5826-13-R4A-F10
108
126
138
150
159
171
5826-13-R4A-G11
108
126
138
150
159
171
5826-13-R4A-G12
111
127
138
151
159
171
5826-13-R4A-H1
110
128
140
146
162
170
5826-13-R4A-H2
108
126
141
149
159
171
5826-13-R4A-H3
108
126
138
149
159
173
5826-13-R4A-H4
112
125
140
146
162
170
5826-13-R4A-H5
108
127
138
147
159
171
5826-13-R4A-H6
108
127
142
147
159
171
5826-13-R4A-H9
108
123
138
149
159
171
5826-13-R4A-H10
110
125
140
146
162
170
5826-13-R4A-H11
110
128
140
146
162
170
5826-13-R4A-H12
110
125
140
146
163
170.
2. A DPP4-binding domain according to claim 1 , comprising:
a) HCVR which comprises the following three CDRs:
V H -CDR1 selected from the group consisting of SEQ ID NO: 109, 108, and 110;
V H -CDR2 selected from the group consisting of SEQ ID NO: 122, 127, and 125;
V H -CDR3 selected from the group consisting of SEQ ID NO: 139, 138, and 140;
b) a LCVR which comprises the following three CDRs:
V L -CDR1 selected from the group consisting of SEQ ID NO: 148, 147, and 146;
V L -CDR2 selected from the group consisting of SEQ ID NO: 160, 159, and 163;
V L -CDR3 selected from the group consisting of SEQ ID NO: 172, 171, and 170.
3. The DPP4-binding domain according to claim 1 , being selected from the group consisting of:
i. DPP4-binding domain comprising a V H -CDR1 with SEQ ID NO: 109, a V H -CDR2 with SEQ ID NO: 122, a V H -CDR3 with SEQ ID NO: 139, a V L -CDR1 with SEQ ID NO: 148, a V L -CDR2 with SEQ ID NO: 160 and a V L -CDR3 with SEQ ID NO: 172;
ii. DPP4-binding domain comprising a V H -CDR1 with SEQ ID NO: 108, a V H -CDR2 with SEQ ID NO: 127, a V H -CDR3 with SEQ ID NO: 138, a V L -CDR1 with SEQ ID NO: 147, a V L -CDR2 with SEQ ID NO: 159 and a V L -CDR3 with SEQ ID NO: 171; and
iii a DPP4-binding domain comprising a V H -CDR1 with SEQ ID NO: 110, a V H -CDR2 with SEQ ID NO: 125, a V H -CDR3 with SEQ ID NO: 140, a V L -CDR1 with SEQ ID NO: 146, a V L -CDR2 with SEQ ID NO: 163 and a V L -CDR3 with SEQ ID NO: 170.
4. The DPP4-binding domain according to claim 1 , being selected from the group consisting of:
i. a DPP4-binding domain comprising a HCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 185 and a LCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 213;
ii. a DPP4-binding domain comprising a HCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 197 and a LCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 212; and
iii. a DPP4-binding domain comprising a HCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 200 and a LCVR with a sequence sharing at least 80% of sequence identity with the non-CDR regions of SEQ ID NO: 227.
5. An isolated antibody or antigen-binding fragment thereof comprising the DPP4-binding domain according to claim 1 .
6. The isolated antibody or antigen-binding fragment thereof-comprising the DPP4-binding domain according to claim 1 , being a bispecific antibody comprising a DPP4-binding domain comprising a combination of three heavy chain variable region (HCVR)'s complementary-determining regions (CDRs) and three light chain variable region (LCVR)'s CDRs, said combination being as defined in claim 1 and an antigen-binding domain to a non-senescent cell-associated antigen.
7. The isolated antibody or antigen-binding fragment thereof comprising the DPP4-binding domain according to claim 1 , being a bispecific antibody comprising the DPP4-binding domain comprising a combination of three heavy chain variable region (HCVR)'s complementary-determining regions (CDRs) and three light chain variable region (LCVR)'s CDRs, said combination being as defined in claim 1 and an antigen-binding domain to another senescent cell-associated antigen.
8. A chimeric antigen receptor (CAR) comprising:
a. at least one extracellular binding domain, comprising at least one DPP4-binding domain according to claim 1 ,
b. an extracellular spacer domain,
c. a transmembrane domain,
d. optionally, at least one costimulatory domain, and
e. at least one intracellular signaling domain.
9. The CAR according to claim 8 , wherein said CAR is multispecific and comprises at least one DPP4-binding domain according to claim 1 and at least one antigen-binding domain to a non-senescent cell-associated antigen.
10. The CAR according to claim 8 , wherein said CAR is multispecific and comprises at least one DPP4-binding domain according to claim 1 and at least one antigen-binding domain to another senescent cell-associated antigen.
11. An immune cell engineered to express the CAR of claim 8 at its surface.
12. A population of immune cells, comprising a plurality of immune cells according to claim 11 .
13. A composition comprising:
the isolated antibody or antigen-binding fragment thereof comprising the DPP4-binding domain according to claim 1 ,
an immune cell engineered to express at its surface a chimeric antigen receptor (CAR) comprising:
(a) at least one extracellular binding domain, comprising at least one DPP4-binding domain, comprising a combination of three heavy chain variable region (HCVR)'s complementary-determining regions (CDRs) and three light chain variable region (LCVR)'s CDRs, said combination being as defined in claim 1 ,
(b) an extracellular spacer domain,
(c) a transmembrane domain,
(d) optionally, at least one costimulatory domain, and
(e) at least one intracellular signaling domain, and/or
a population of immune cells comprising a plurality of immune cells engineered to express at each cell's surface a chimeric antigen receptor (CAR) comprising:
(a) at least one extracellular binding domain, comprising at least one DPP4-binding domain, comprising a combination of three heavy chain variable region (HCVR)'s complementary-determining regions (CDRs) and three light chain variable region (LCVR)'s CDRs, said combination being as defined in claim 1 ,
(b) an extracellular spacer domain,
(c) a transmembrane domain,
(d) optionally, at least one costimulatory domain, and
(e) at least one intracellular signaling domain.
14. The composition according to claim 13 , being a pharmaceutical composition and further comprising at least one pharmaceutically acceptable excipient.
15. A method of depleting and/or killing senescent cells, comprising contacting the senescent cells with the composition according to claim 13 .