Monoclonal antibodies against BCMA
The invention relates to new antibodies against BCMA, their manufacture and use.
1. A monoclonal antibody specifically binding to human B cell maturation antigen (BCMA), characterized in comprising a CDR3H region having SEQ ID NO:17 and a CDR3L region having SEQ ID NO:20 and a CDR1H, CDR2H, CDR1L, and CDR2L region combination selected from the group of:
a) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:23, and CDR2L region having SEQ ID NO:24,
b) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:25, and CDR2L region having SEQ ID NO:26,
c) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:27, and CDR2L region having SEQ ID NO:28,
d) CDR1H region having SEQ ID NO:29 and CDR2H region having SEQ ID NO:30, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32,
e) CDR1H region having SEQ ID NO:34 and CDR2H region having SEQ ID NO:35, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, and
f) CDR1H region having SEQ ID NO:36 and CDR2H region having SEQ ID NO:37, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32.
2. A monoclonal antibody specifically binding to BCMA, characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17 and a VL region comprising a CDR3L region having SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of:
a) CDR1L region having SEQ ID NO:23 and CDR2L region having SEQ ID NO:24,
b) CDR1L region having SEQ ID NO:25 and CDR2L region having SEQ ID NO:26, and
c) CDR1L region having SEQ ID NO:27 and CDR2L region having SEQ ID NO:28.
3. The antibody according to claim 2 , characterized in comprising a VH region having SEQ ID NO:10 and a VL region selected from the group consisting of VL regions having SEQ ID NO:12, 13, and 14.
4. A bispecific antibody specifically binding to BCMA and human CD3ε (CD3), characterized in comprising a CDR3H region having SEQ ID NO:17 and a CDR3L region having SEQ ID NO:20 and a CDR1H, CDR2H, CDR1L, and CDR2L region combination selected from the group of:
a) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:23, and CDR2L region having SEQ ID NO:24,
b) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:25, and CDR2L region having SEQ ID NO:26,
c) CDR1H region having SEQ ID NO:21 and CDR2H region having SEQ ID NO:22, CDR1L region having SEQ ID NO:27, and CDR2L region having SEQ ID NO:28,
d) CDR1H region having SEQ ID NO:29 and CDR2H region having SEQ ID NO:30, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32,
e) CDR1H region having SEQ ID NO:34 and CDR2H region having SEQ ID NO:35, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32, and
f) CDR1H region having SEQ ID NO:36 and CDR2H region having SEQ ID NO:37, CDR1L region having SEQ ID NO:31, and CDR2L region having SEQ ID NO:32.
5. A bispecific antibody specifically binding to two targets which are the extracellular domain of human BCMA (BCMA) and human CD3ε (CD3), characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17 and a VL region comprising a CDR3L region having SEQ ID NO:20 and a CDR1L and CDR2L region combination selected from the group of:
a) CDR1L region having SEQ ID NO:23 and CDR2L region having SEQ ID NO:24,
b) CDR1L region having SEQ ID NO:25 and CDR2L region having SEQ ID NO:26, and
c) CDR1L region having SEQ ID NO:27 and CDR2L region having SEQ ID NO:28.
6. The bispecific antibody according to claim 5 , characterized in comprising a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:12, or a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:13, or a BCMA VH region having SEQ ID NO:10 and a VL region having SEQ ID NO:14.
7. The bispecific antibody according to claim 4 , characterized in comprising a light chain and a heavy chain of an antibody specifically binding to CD3, wherein the variable domains VL and VH or the constant domains CL and CH1 are replaced by each other.
8. The bispecific antibody according to claim 4 , characterized in that a variable domain VH of an anti-CD3 antibody portion of the bispecific antibody (CD3 VH) comprises heavy chain CDRs having SEQ ID NO: 1, 2 and 3 as respective heavy chain CDR1, CDR2 and CDR3 and the variable domain VL of the anti-CD3 antibody portion (CD3 VL) comprises light chain CDRs having SEQ ID NO: 4, 5 and 6 as respective light chain CDR1, CDR2 and CDR3.
9. A bispecific antibody specifically binding to BCMA and CD3, characterized in comprising
a) a first light chain and a first heavy chain of a first anti-BCMA antibody according to claim 1 ; and
b) a second light chain and a second heavy chain of a second antibody which specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and second heavy chain of the second antibody are replaced by each other; and
c) wherein in a constant domain CL of the first light chain a) an amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in a constant domain CH1 of the first heavy chain a) an amino acid at position 147 and an amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat).
10. A bispecific antibody according to claim 9 , characterized in comprising in addition a Fab fragment of said first antibody (BCMA-Fab) and in the constant domain CL of said BCMA-Fab the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in the constant domain CH1 of said BCMA-Fab the amino acid at positions 147 and the amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat) (see e.g. FIGS. 2A, 2C ).
11. A bispecific antibody specifically binding to BCMA and CD3, characterized in comprising
a) a first light chain and a first heavy chain of a first antibody according to claim 1 ; and
b) a second light chain and a second heavy chain of a second antibody which specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and second heavy chain of the second antibody are replaced by each other; and wherein
c) in a constant domain CL of the second light chain under b) an amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and wherein in a constant domain CH1 of the second heavy chain under b) an amino acid at positions 147 and an amino acid at position 213 are substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to EU index of Kabat).
12. The bispecific antibody according to claim 4 , characterized in comprising not more than one Fab fragment of an anti-CD3 antibody, not more than two Fab fragments of an anti-BCMA antibody and not more than one Fc part.
13. The bispecific antibody according to claim 12 characterized in comprising an Fc part linked with its N-terminus to the C-terminus of said CD3 antibody Fab fragment and to the C-terminus of one of said BCMA antibody Fab fragments.
14. The bispecific antibody according to claim 13 , characterized in comprising a second Fab fragment of said anti-BCMA antibody portion linked with its C-terminus to the N-terminus of the CD3 antibody portion of said bispecific antibody.
15. The bispecific antibody according to claim 14 , characterized in that a VL domain of said anti-CD3 antibody Fab fragment is linked to a CH1 domain of said second anti-BCMA antibody Fab fragment.
16. A bispecific antibody specifically binding to BCMA and to CD3, characterized in comprising a heavy and light chain set selected from the group consisting of polypeptides:
i) SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51 (2×),
ii) SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54 (2×), or
iii) SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56, and SEQ ID NO:57 (2×).
17. A method of treatment of a plasma cell disorder comprising administering an antibody according to claim 1 to a subject in need thereof.
18. A method of treatment of a plasma cell disorder according to claim 17 wherein the plasma cell disorder is selected from the group consisting of multiple myeloma, systemic lupus erythematosus, plasma cell leukemia, and AL-amyloidosis.
19. A chimeric antigen receptor (CAR), wherein the CAR comprises an antigen recognition moiety directed against BCMA and a T-cell activation moiety, characterized in that the antigen recognition moiety is a monoclonal antibody or antibody fragment according to claim 1 .
20. A monoclonal antibody specifically binding to BCMA according to claim 1 , characterized in comprising a VH region comprising a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17; and a VL region comprising a CDR1L region having SEQ ID NO:27, a CDR2L region having SEQ ID NO:28 and a CDR3L region having SEQ ID NO:20.
21. A bispecific antibody specifically binding to BCMA and human CD3E (CD3) according to claim 4 , characterized in that a variable domain VH of an anti-BCMA antibody portion of the bispecific antibody comprises a CDR1H region having SEQ ID NO:21, a CDR2H region having SEQ ID NO:22 and a CDR3H region having SEQ ID NO:17; and a VL region comprising a CDR1L region having SEQ ID NO:27, a CDR2L region having SEQ ID NO:28 and a CDR3L region having SEQ ID NO:20; and,
wherein the bispecific antibody is further characterized in that a variable domain VH of a n anti-CD3 antibody portion of the bispecific antibody comprises a CDR1H region having SEQ ID NO:1, a CDR2H region having SEQ ID NO:2 and a CDR3H region having SEQ ID NO:3; and a VL region comprising a CDR1L region having SEQ ID NO:4, a CDR2L region having SEQ ID NO:5 and a CDR3L region having SEQ ID NO:6.