Antigen binding proteins that bind BCMA
The present disclosure provides BCMA binding proteins, particularly anti-BCMA antibodies, or antigen-binding portions thereof, that specifically bind BCMA and uses thereof. In one embodiment, the anti-BCMA antibody comprises an antigen binding portion that binds a human BCMA epitope and blocks binding (e.g, inhibits binding) of human APRIL and/or human BAFF to the human BCMA epitope. Various aspects of the anti-BCMA antibodies relate to antibody fragments, single-chain antibodies, pharmaceutical compositions, nucleic acids, recombinant expression vectors, host cells, and methods for preparing and using such anti-BCMA antibodies. Methods for using the anti-BCMA antibodies include in vitro and in vivo methods for binding BCMA, detecting BCMA and treating diseases associated with BCMA over-expression.
1 . A fully human anti-BCMA antibody, or an antigen-binding fragment thereof, comprising a heavy chain and a light chain,
wherein (a) the heavy chain comprises: a heavy chain complementarity determining region 1 (CDR1) having the amino acid sequence of SEQ ID NO:29, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:30, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:31; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:32, a light chain CDR2 having the amino acid sequence of SEQ ID NO:33, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:34;
wherein (b) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:35, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:36, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:37; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:38, a light chain CDR2 having the amino acid sequence of SEQ ID NO:39, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:40;
wherein (c) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:41, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:42, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:43; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:44, a light chain CDR2 having the amino acid sequence of SEQ ID NO:45, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:46;
wherein (d) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:47, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:48, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:49; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:50, a light chain CDR2 having the amino acid sequence of SEQ ID NO:51, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:52;
wherein (e) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:53, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:54, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:55; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:56, a light chain CDR2 having the amino acid sequence of SEQ ID NO:57, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:58;
wherein (f) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:59, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:60, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:61; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:62, a light chain CDR2 having the amino acid sequence of SEQ ID NO:63, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:64;
wherein (g) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:65, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:66, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:67; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:68, a light chain CDR2 having the amino acid sequence of SEQ ID NO:69, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:70;
wherein (h) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:71, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:72, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:73; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:74, a light chain CDR2 having the amino acid sequence of SEQ ID NO:75, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:76;
wherein (i) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:77, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:78, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:79; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:80, a light chain CDR2 having the amino acid sequence of SEQ ID NO:81, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:82;
wherein (j) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:83, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:84, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:85; and the light chain comprises: a light chain CDR1 having the amino acid sequence of SEQ ID NO:86, a light chain CDR2 having the amino acid sequence of SEQ ID NO:87, and a light chain CDR3 having the amino acid sequence of SEQ ID NO:88; or
wherein (k) the heavy chain comprises: a heavy chain CDR1 having the amino acid sequence of SEQ ID NO:53, a heavy chain CDR2 having the amino acid sequence of SEQ ID NO:54, a heavy chain CDR3 having the amino acid sequence of SEQ ID NO:55; and the light chain comprises: a lambda light chain CDR1 having the amino acid sequence of SEQ ID NO:89, a lambda light chain CDR2 having the amino acid sequence of SEQ ID NO:90, and a lambda light chain CDR3 having the amino acid sequence of SEQ ID NO:91.
2 . A fully human anti-BCMA antibody, or antigen-binding fragment thereof, of claim 1 comprising a heavy chain and a light chain, the heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8, 10, 12, 14 or 22, and the light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9, 11, 13, 15, 16, 17, 18, 19, 20, 21 or 23.
3 . A fully human anti-BCMA antibody, or the antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region comprise the amino acid sequences of SEQ ID NO: 8 and 9; SEQ ID NO: 10 and 11; SEQ ID NO: 12 and 13; SEQ ID NO: 14 and 15; SEQ ID NO: 8 and 16; SEQ ID NO: 8 and 17; SEQ ID NO: 8 and 18; SEQ ID NO: 8 and 19; SEQ ID NO: 8 and 20; SEQ ID NO: 8 and 21; or SEQ ID NO: 22 and 23.
4 . The antigen-binding fragment of claim 2 , comprising a Fab fragment having a variable domain region from a heavy chain and a variable domain region from a light chain, wherein the variable domain region from the heavy chain comprises a sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8, 10, 12, 14 or 22, and wherein the variable domain region from the light chain comprises a sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9, 11, 13, 15, 16, 17, 18, 19, 20, 21 or 23.
5 . The antigen-binding fragment of claim 2 , comprising a single chain antibody comprising a variable domain region from a heavy chain and a variable domain region from a light chain joined together with a peptide linker, wherein the variable domain region from the heavy chain comprises a sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8, 10, 12, 14 or 22, and wherein the variable domain region from the light chain comprises a sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9, 11, 13, 15, 16, 17, 18, 19, 20, 21 or 23.
6 . The fully human anti-BCMA antibody of claim 2 , comprising an IgG1, IgG2, IgG3 or IgG4 class antibody.
7 . The antibody or antigen-binding fragment of claim 1 , that blocks binding between APRIL (A PRoliferation-Inducing Ligand) protein and BCMA protein.
8 . The antibody or antigen-binding fragment of claim 1 , that binds to BCMA proteins from human, cynomolgus and mouse.
9 . The antibody or antigen-binding fragment of claim 1 , that binds to cells expressing BCMA protein.
10 . The antibody or antigen-binding fragment of claim 1 , that binds to human myeloma cells expressing BCMA protein.
11 . A pharmaceutical composition, comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically-acceptable excipient.
12 . A first nucleic acid encoding a first polypeptide comprising the antibody heavy chain variable region of claim 2 , wherein the amino acid sequence of the antibody heavy chain variable region has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8, 10, 12, 14 or 22, and a second nucleic acid encoding a second polypeptide comprising the antibody light chain variable region of claim 2 , wherein the amino acid sequence of the antibody light chain variable region has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 9, 11, 13, 15, 16, 17, 18, 19, 20, 21 or 23.
13 . One or more nucleic acids encoding the antibody or antigen-binding fragment of claim 1 .
14 . One or more expression vectors comprising one or more promoters operably linked to the first and second nucleic acids of claim 12 .
15 . One or more expression vectors comprising one or more promoters operably linked to the one or more nucleic acids of claim 13 .
16 . A host cell harboring the one or more expression vectors of claim 15 .
17 . A method for preparing the first polypeptide comprising the antibody heavy chain variable region and the second polypeptide comprising the antibody light chain variable region or the antibody or antigen-binding fragment, the method comprising: culturing a population (a plurality) of the host cell of claim 16 under conditions suitable for expressing the first polypeptide and the second polypeptide or the antibody or antigen-binding fragment.
18 . The method of claim 17 , further comprising: recovering from the population of the host cell the expressed first polypeptide and the expressed second polypeptide or the expressed antibody or antigen-binding fragment.