Bi-specific T-cell engager specific for BCMA
The present invention provides a bi-specific molecule which comprises: (i) a first domain which binds B cell maturation antigen (BCMA) and comprises at least part of a proliferation-inducing ligand (APRIL); and (ii) a second domain capable of activating a T cell. The invention also provides the use of such a molecule in the treatment of plasma-cell mediated diseases, such as multiple myeloma.
1. A bi-specific T-cell engager which comprises:
(i) a first domain which comprises a truncated A proliferation-inducing ligand (APRIL)/TNF Superfamily Member 13 Protein (TNFSF13), which comprises the BCMA binding site of APRIL, wherein truncated APRIL comprises the sequence shown as SEQ ID No. 2 or a sequence which has at least 90% sequence identity to SEQ ID No. 2 and binds BCMA; and
(ii) a second domain which comprises a CD3-specific antibody or an antigen binding fragment thereof comprising complementarity determining regions (CDRs) from an scFv sequence shown as SEQ ID No. 9;
wherein said first domain and said second domain are connected by a spacer.
2. A bi-specific T-cell engager according to claim 1 , wherein the second domain comprises the scFv sequence shown as SEQ ID No. 9 or a sequence which has at least 90% sequence identity to SEQ ID No. 9 and comprises the complementarity determining regions (CDRs) from SEQ ID No. 9 and binds CD3.
3. A bi-specific T-cell engager according to claim 1 , wherein the spacer comprises an IgG1 hinge or a CD8 stalk.
4. A bi-specific T-cell engager according to claim 1 , which comprises the sequence shown as SEQ ID No. 10, 11 or 12 or a sequence which has at least 90% sequence identity to SEQ ID No. 10, 11 or 12 and comprises the CDRs from the sequence of SEQ ID No. 10, 11 or 12, and wherein the bispecific T-cell engager i) binds BCMA and ii) activates a T cell.
5. A bi-specific T-cell engager according to claim 1 , which binds to BCMA in a three-fold subunit cluster.
6. A pharmaceutical composition which comprises a bi-specific T-cell engager according to claim 1 , together with a pharmaceutically acceptable carrier, diluent or excipient.
7. A nucleic acid sequence which encodes a bi-specific T-cell engager according to claim 1 .
8. A nucleic acid sequence according to claim 7 which comprises the sequence shown as SEQ ID No 19, 20 or 21 or a variant thereof having at least 80% sequence identity to SEQ ID No 19, 20 or 21 and which encodes the CDRs from the sequence of SEQ ID No. 10, 11 or 12, and wherein the encoded bispecific T-cell engager i) binds BCMA and ii) activates a T cell.
9. A vector which comprises a nucleic acid sequence according to claim 7 .
10. A host cell which comprises a nucleic acid sequence according to claim 7 and expresses a bi-specific T-cell engager.
11. A method for producing a bi-specific T-cell engager which comprises the step of culturing a host cell of claim 10 under conditions such that the bi-specific T-cell engager is produced.