Therapeutic antibodies and their uses
The present invention relates to bispecific antibodies that specific bind to BCMA (B-Cell Maturation Antigen) and CD3 (Cluster of Differentiation 3). Method of making the bispecific antibodies and method of using the bispecific antibodies for the treatment of multiple myeloma are also provided.
1. A bispecific antibody comprising a first antibody variable domain and a second antibody variable domain, wherein the first antibody variable domain specifically binds to Cluster of Differentiation 3 (CD3), the second antibody variable domain specifically binds to B-Cell Maturation Antigen (BCMA), and wherein
(a) the first antibody variable domain comprises a heavy chain variable region complementarity determining region one (VH CDR1) comprising the sequence shown in SEQ ID NO: 333; a VH CDR2 comprising the sequence shown in SEQ ID NO: 417; a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; a light chain variable region CDR1 (VL CDR1) comprising the sequence shown in SEQ ID NO: 343; a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 157; a VH CDR2 comprising the sequence shown in SEQ ID NO: 159; a VH CDR3 comprising the sequence shown in SEQ ID NO: 155; a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 225;
(b) the first antibody variable domain comprises a heavy chain variable region complementarity determining region one (VH CDR1) comprising the sequence shown in SEQ ID NO: 331; a VH CDR2 comprising the sequence shown in SEQ ID NO: 336; a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; a light chain variable region CDR1 (VL CDR1) comprising the sequence shown in SEQ ID NO: 343; a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 156; a VH CDR2 comprising the sequence shown in SEQ ID NO:158; a VH CDR3 comprising the sequence shown in SEQ ID NO: 155; a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 225;
(c) the first antibody variable domain comprises a heavy chain variable region complementarity determining region one (VH CDR1) comprising the sequence shown in SEQ ID NO: 332; a VH CDR2 comprising the sequence shown in SEQ ID NO: 417; a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; a light chain variable region CDR1 (VL CDR1) comprising the sequence shown in SEQ ID NO: 343; a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 151; a VH CDR2 comprising the sequence shown in SEQ ID NO:159; a VH CDR3 comprising the sequence shown in SEQ ID NO: 155; a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 225; or
(d) the first antibody variable domain comprises a heavy chain variable region complementarity determining region one (VH CDR1) comprising the sequence shown in SEQ ID NO: 333; a VH CDR2 comprising the sequence shown in SEQ ID NO: 336; a VH CDR3 comprising the sequence shown in SEQ ID NO: 335; a light chain variable region CDR1 (VL CDR1) comprising the sequence shown in SEQ ID NO: 343; a VL CDR2 comprising the sequence shown in SEQ ID NO: 341; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 342; and the second antibody variable domain comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 157; a VH CDR2 comprising the sequence shown in SEQ ID NO:158; a VH CDR3 comprising the sequence shown in SEQ ID NO: 155; a VL CDR1 comprising the sequence shown in SEQ ID NO: 209; a VL CDR2 comprising the sequence shown in SEQ ID NO: 221; and a VL CDR3 comprising the sequence shown in SEQ ID NO: 225.
2. The bispecific antibody of claim 1 , wherein the second antibody variable domain comprises a VH CDR2 comprising the sequence shown in SEQ ID NO: 159.
3. The bispecific antibody of claim 1 , wherein the bispecific antibody further comprises a human IgG2 heavy chain constant region.
4. The bispecific antibody of claim 3 , wherein the human IgG2 heavy chain constant region is a modified human IgG2 heavy chain constant region, as compared to a wild type human IgG2 heavy chain constant region.
5. The bispecific antibody of claim 3 , wherein the bispecific antibody comprises two human IgG2 heavy chain constant regions, wherein one heavy chain constant region comprises the sequence shown in SEQ ID NO: 496 and the other heavy chain constant region comprises the sequence shown in SEQ ID NO: 497.
6. The bispecific antibody of claim 1 , further comprising two heavy chain constant regions, wherein one heavy chain constant region comprises the sequence shown in SEQ ID NO: 496.
7. The bispecific antibody of claim 1 , further comprising two heavy chain constant regions, wherein one heavy chain constant region comprises the sequence shown in SEQ ID NO: 497.
8. The bispecific antibody of claim 1 , wherein the first antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 324, and a light chain variable region comprising the sequence shown in SEQ ID NO: 323; and
the second antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 112, and a light chain variable region comprising the sequence shown in SEQ ID NO: 38.
9. The bispecific antibody of claim 1 , wherein the first antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 324, and a light chain variable region comprising the sequence shown in SEQ ID NO: 323; and
the second antibody variable domain comprises a heavy chain variable region encoded by the polynucleotide sequence shown in SEQ ID NO: 486, and a light chain variable region encoded by the polynucleotide sequence shown in SEQ ID NO: 485.
10. The bispecific antibody of claim 9 , further comprising two heavy chain constant regions, wherein one heavy chain constant region comprises the sequence shown in SEQ ID NO: 496 and the other heavy chain constant region comprises the sequence shown in SEQ ID NO: 497.
11. The bispecific antibody of claim 1 , wherein
the first antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 324, and a light chain variable region comprising the sequence shown in SEQ ID NO: 323; and
the second antibody variable domain comprises a heavy chain variable region encoded by the polynucleotide having ATCC Accession No. PTA-122094, and a light chain variable region encoded by the polynucleotide having ATCC Accession No. PTA-122093.
12. The bispecific antibody of claim 11 , further comprising two heavy chain constant regions, wherein one heavy chain constant region comprises the sequence shown in SEQ ID NO: 496 and the other heavy chain constant region comprises the sequence shown in SEQ ID NO: 497.
13. A bispecific antibody comprising a first antibody variable domain and a second antibody variable domain, wherein
the first antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 324, and a light chain variable region comprising the sequence shown in SEQ ID NO: 323; and
the second antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 112, and a light chain variable region comprising the sequence shown in SEQ ID NO: 38.
14. A bispecific antibody comprising a first antibody variable domain and a second antibody variable domain, wherein
the first antibody variable domain comprises a heavy chain variable region comprising the sequence shown in SEQ ID NO: 324, and a light chain variable region comprising the sequence shown in SEQ ID NO: 323; and
the second antibody variable domain comprises a heavy chain variable region encoded by the polynucleotide sequence shown in SEQ ID NO: 486, and a light chain variable region encoded by the polynucleotide sequence shown in SEQ ID NO: 485.