Antibody against human DLK1 and use thereof
The present invention relates to an antibody against delta-like 1 homolog ( Drosophila ) (DLK1) or an antigen-binding fragment thereof, a nucleic acid encoding the same, a vector comprising the nucleic acid, a cell transformed with the vector, a method for producing the antibody or an antigen-binding fragment thereof, an antibody drug conjugate (ADC) comprising the same, a pharmaceutical composition for treating cancer, a composition for diagnosing cancer, and a chimeric antigen receptor (CAR) and a T-cell engager comprising the same.
1. An antibody or an antigen-binding fragment thereof specifically binding to delta-like 1 homolog (DLK1), comprising the following heavy-chain variable region and light-chain variable region:
a heavy-chain variable region comprising heavy-chain CDR1 of SEQ ID. NO: 16, heavy-chain CDR2 of SEQ ID. NO: 18, heavy-chain CDR3 of SEQ ID. NO: 20, a light-chain variable region comprising light-chain CDR1 of SEQ ID. NO: 23, light-chain CDR2 of SEQ ID. NO: 25, light-chain CDR3 of SEQ ID. NO: 27,
a heavy-chain variable region comprising heavy-chain CDR1 of SEQ ID. NO: 72, heavy-chain CDR2 of SEQ ID. NO: 74, heavy-chain CDR3 of SEQ ID. NO: 76, a light-chain variable region comprising light-chain CDR1 of SEQ ID. NO: 79, light-chain CDR2 of SEQ ID. NO: 81, light-chain CDR3 of SEQ ID. NO: 83,
a heavy-chain variable region comprising heavy-chain CDR1 of SEQ ID. NO: 16, heavy-chain CDR2 of SEQ ID. NO: 18, heavy-chain CDR3 of SEQ ID. NO: 20, a light-chain variable region comprising light-chain CDR1 of SEQ ID. NO: 115, light-chain CDR2 of SEQ ID. NO: 95, light-chain CDR3 of SEQ ID. NO: 116, or
a heavy-chain variable region comprising heavy-chain CDR1 of SEQ ID. NO: 16, heavy-chain CDR2 of SEQ ID. NO: 18, heavy-chain CDR3 of SEQ ID. NO: 20, a light-chain variable region comprising light-chain CDR1 of SEQ ID. NO: 121, light-chain CDR2 of SEQ ID. NO: 39, light-chain CDR3 of SEQ ID. NO: 124.
2. The antibody or an antigen-binding fragment thereof according to claim 1 , comprising:
heavy chain FR1 selected from the group consisting of SEQ ID NOS: 1, 15, 29, 43, 57, 71, 85, and 119;
heavy chain FR2 selected from the group consisting of SEQ ID NOS: 3, 17, 31, 45, 59, 73, and 87;
heavy chain FR3 selected from the group consisting of SEQ ID NOS: 5, 19, 33, 47, 61, 75, and 89;
heavy chain FR4 selected from the group consisting of SEQ ID NOS: 7, 21, 35, 49, 63, 77, and 91;
light chain FR1 selected from the group consisting of SEQ ID NOS: 8, 22, 36, 50, 64, 78, 92, 117, and 120;
light chain FR2 selected from the group consisting of SEQ ID NOS: 10, 24, 38, 52, 66, 80, 94, and 122;
light chain FR3 selected from the group SEQ ID NOS: 12, 26, 40, 54, 68, 82, 96, 118, and 123; or
light chain FR4 selected from the group consisting of SEQ ID NO: 14, 28, 42, 56, 70, 84, 98, and 125.
3. The antibody or an antigen-binding fragment thereof according to claim 1 , comprising a heavy-chain variable region having a sequence selected from the group consisting of SEQ ID NOS: 101, 109, and 127.
4. The antibody or an antigen-binding fragment thereof according to claim 1 , comprising a light-chain variable region having a sequence selected from the group consisting of SEQ ID NOS: 102, 110, 126, and 128.
5. A nucleic acid encoding the antibody or an antigen-binding fragment thereof according to claim 1 .
6. An expression vector comprising the nucleic acid according to claim 5 .
7. A cell transformed with the expression vector according to claim 6 .
8. A method of producing an antibody or an antigen-binding fragment thereof specifically binding to DLK1 comprising:
(a) culturing the cells according to claim 7 ; and
(b) recovering an antibody or an antigen-binding fragment thereof from the cell culture.
9. An antibody-drug conjugate (ADC) comprising the antibody or an antigen-binding fragment thereof according to claim 1 , and a drug.
10. The antibody-drug conjugate (ADC) according to claim 9 , wherein the drug is selected from the group consisting of cytotoxins, radioisotopes, antiproliferative agents, pro-apoptotic agents, chemotherapeutic agents, and therapeutic nucleic acids.
11. A pharmaceutical composition comprising, as an active ingredient, the antibody or an antigen-binding fragment thereof according to the antibody-drug conjugate according to claim 9 .
12. A bispecific antibody comprising the antibody or an antigen-binding fragment thereof according to claim 1 .
13. A pharmaceutical composition comprising, as an active ingredient, the antibody or an antigen-binding fragment thereof according to the bispecific antibody according to claim 12 .
14. A pharmaceutical composition comprising, as an active ingredient, the antibody or an antigen-binding fragment thereof according to claim 1 .
15. A chimeric antigen receptor (CAR) comprising the antibody or an antigen-binding fragment thereof according to claim 1 as an antigen-binding domain.
16. A T-cell engager comprising the antibody or an antigen-binding fragment thereof according to claim 1 , specifically binding to DLK1 expressed in tumor cells.
17. The antibody or an antigen-binding fragment thereof according to claim 1 , comprising
a heavy-chain variable region including a sequence of SEQ ID NO: 101, and a light-chain variable region including a sequence of SEQ ID NO: 102,
a heavy-chain variable region including a sequence of SEQ ID NO: 109, and a light-chain variable region including a sequence of SEQ ID NO: 110,
a heavy-chain variable region including a sequence of SEQ ID NO: 101, and a light-chain variable region including a sequence of SEQ ID NO: 126, or
a heavy-chain variable region including a sequence of SEQ ID NO: 127, and a light-chain variable region including a sequence of SEQ ID NO: 128.