Method for the selection of antibodies against bcma

Abstract

An antibody specifically binding to human BCMA, characterized in that the binding of said antibody is not reduced by APRIL and not reduced by BAFF, said antibody does not alter APRIL-dependent NF-κB activation, BAFF-dependent NF-κB activation, and does not alter NF-κB activation without BAFF and APRIL is useful as a therapeutic agent.

1 .- 21 . (canceled) 
     
     
         22 . An antibody specifically binding to human B cell maturation factor (BCMA), wherein said antibody comprises variable heavy and light domains VH and VL of an antibody specifically binding to BCMA wherein:
 a. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:37, a CDR2H comprising the amino acid sequence of SEQ ID NO:47 and a CDR3H comprising the amino acid sequence of SEQ ID NO:57 and the variable domain VL comprises a CDR1L comprising the amino acid sequence of SEQ ID NO:67, a CDR2L comprising the amino acid sequence of SEQ ID NO:77 and a CDR3L comprising the amino acid sequence of SEQ ID NO:87;   b. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:38, a CDR2H comprising the amino acid sequence of SEQ ID NO:48 and a CDR3H comprising the amino acid sequence of SEQ ID NO:58 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:68, a CDR2L comprising the amino acid sequence of SEQ ID NO:78 and a CDR3L comprising the amino acid sequence of SEQ ID NO:88;   c. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:40, a CDR2H comprising the amino acid sequence of SEQ ID NO:50 and a CDR3H comprising the amino acid sequence of SEQ ID NO:60 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:70, a CDR2L comprising the amino acid sequence of SEQ ID NO:80 and a CDR3L comprising the amino acid sequence of SEQ ID NO:90;   d. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:41, a CDR2H comprising the amino acid sequence of SEQ ID NO:51 and a CDR3H comprising the amino acid sequence of SEQ ID NO:61 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:71, a CDR2L comprising the amino acid sequence of SEQ ID NO:81 and a CDR3L comprising the amino acid sequence of SEQ ID NO:91;   e. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:42, a CDR2H comprising the amino acid sequence of SEQ ID NO:52 and a CDR3H comprising the amino acid sequence of SEQ ID NO:62 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:72, a CDR2L comprising the amino acid sequence of SEQ ID NO:82 and a CDR3L comprising the amino acid sequence of SEQ ID NO:92;   f. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:43, a CDR2H comprising the amino acid sequence of SEQ ID NO:53 and a CDR3H comprising the amino acid sequence of SEQ ID NO:63 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:73, a CDR2L comprising the amino acid sequence of SEQ ID NO:83 and a CDR3L comprising the amino acid sequence of SEQ ID NO:93;   g. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:44, a CDR2H comprising the amino acid sequence of SEQ ID NO:54 and a CDR3H comprising the amino acid sequence of SEQ ID NO:64 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:74, a CDR2L comprising the amino acid sequence of SEQ ID NO:84 and a CDR3L comprising the amino acid sequence of SEQ ID NO:94;   h. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:45, a CDR2H comprising the amino acid sequence of SEQ ID NO:55 and a CDR3H comprising the amino acid sequence of SEQ ID NO:65 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:75, a CDR2L comprising the amino acid sequence of SEQ ID NO:85 and a CDR3L comprising the amino acid sequence of SEQ ID NO:95; or   i. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:46, a CDR2H comprising the amino acid sequence of SEQ ID NO:56 and a CDR3H comprising the amino acid sequence of SEQ ID NO:66 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:76, a CDR2L comprising the amino acid sequence of SEQ ID NO:86 and a CDR3L comprising the amino acid sequence of SEQ ID NO:96.   
     
     
         23 . The antibody of  claim 22 , wherein said antibody is a bispecific antibody. 
     
     
         24 . The antibody of  claim 23 , wherein said bispecific antibody additionally binds CD3. 
     
     
         25 . The antibody of  claim 24 , wherein said bispecific antibody comprises the variable heavy and light chains of anti-CD3 antibody SP34. 
     
     
         26 . A pharmaceutical composition comprising the antibody of  claim 22 , and a pharmaceutically acceptable excipient. 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein said antibody is a bispecific antibody. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said bispecific antibody additionally binds CD3. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein said bispecific antibody comprises the variable heavy and light chains of anti-CD3 antibody SP34. 
     
     
         30 . A method of treating multiple myeloma comprising administering to a subject in need thereof an antibody that comprises variable heavy and light chains VH and VL of an antibody specifically binding to BCMA wherein:
 a. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:37, a CDR2H comprising the amino acid sequence of SEQ ID NO:47 and a CDR3H comprising the amino acid sequence of SEQ ID NO:57 and the variable domain VL comprises a CDR1L comprising the amino acid sequence of SEQ ID NO:67, a CDR2L comprising the amino acid sequence of SEQ ID NO:77 and a CDR3L comprising the amino acid sequence of SEQ ID NO:87;   b. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:38, a CDR2H comprising the amino acid sequence of SEQ ID NO:48 and a CDR3H comprising the amino acid sequence of SEQ ID NO:58 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:68, a CDR2L comprising the amino acid sequence of SEQ ID NO:78 and a CDR3L comprising the amino acid sequence of SEQ ID NO:88;   c. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:39, a CDR2H comprising the amino acid sequence of SEQ ID NO:49 and a CDR3H comprising the amino acid sequence of SEQ ID NO:59 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:69, a CDR2L comprising the amino acid sequence of SEQ ID NO:79 and a CDR3L comprising the amino acid sequence of SEQ ID NO:89;   d. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:40, a CDR2H comprising the amino acid sequence of SEQ ID NO:50 and a CDR3H comprising the amino acid sequence of SEQ ID NO:60 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:70, a CDR2L comprising the amino acid sequence of SEQ ID NO:80 and a CDR3L comprising the amino acid sequence of SEQ ID NO:90;   e. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:41, a CDR2H comprising the amino acid sequence of SEQ ID NO:51 and a CDR3H comprising the amino acid sequence of SEQ ID NO:61 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:71, a CDR2L comprising the amino acid sequence of SEQ ID NO:81 and a CDR3L comprising the amino acid sequence of SEQ ID NO:91;   f. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:42, a CDR2H comprising the amino acid sequence of SEQ ID NO:52 and a CDR3H comprising the amino acid sequence of SEQ ID NO:62 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:72, a CDR2L comprising the amino acid sequence of SEQ ID NO:82 and a CDR3L comprising the amino acid sequence of SEQ ID NO:92;   g. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:43, a CDR2H comprising the amino acid sequence of SEQ ID NO:53 and a CDR3H comprising the amino acid sequence of SEQ ID NO:63 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:73, a CDR2L comprising the amino acid sequence of SEQ ID NO:83 and a CDR3L comprising the amino acid sequence of SEQ ID NO:93;   h. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:44, a CDR2H comprising the amino acid sequence of SEQ ID NO:54 and a CDR3H comprising the amino acid sequence of SEQ ID NO:64 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:74, a CDR2L comprising the amino acid sequence of SEQ ID NO:84 and a CDR3L comprising the amino acid sequence of SEQ ID NO:94;   i. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:45, a CDR2H comprising the amino acid sequence of SEQ ID NO:55 and a CDR3H comprising the amino acid sequence of SEQ ID NO:65 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:75, a CDR2L comprising the amino acid sequence of SEQ ID NO:85 and a CDR3L comprising the amino acid sequence of SEQ ID NO:95; or   j. the variable domain VH comprises a CDR1H comprising the amino acid sequence of SEQ ID NO:46, a CDR2H comprising the amino acid sequence of SEQ ID NO:56 and a CDR3H comprising the amino acid sequence of SEQ ID NO:66 and the variable domain VL comprises the amino acid sequence of a CDR1L comprising the amino acid sequence of SEQ ID NO:76, a CDR2L comprising the amino acid sequence of SEQ ID NO:86 and a CDR3L comprising the amino acid sequence of SEQ ID NO:96.   
     
     
         31 . The method of  claim 30 , wherein said antibody is a bispecific antibody. 
     
     
         32 . The method of  claim 31 , wherein said bispecific antibody additionally binds CD3. 
     
     
         33 . The method of  claim 32 , wherein said bispecific antibody comprises the variable heavy and light chains of anti-CD3 antibody SP34. 
     
     
         34 . The method of  claim 30 , wherein:
 a. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 17 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 27;   b. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 18 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 28;   c. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 19 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 29;   d. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 20 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 30;   e. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 21 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 31;   f. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 22 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 32;   g. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 23 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 33;   h. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 24 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 34;   i. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 25 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 35; or   j. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 26 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 36.   
     
     
         35 . The method of  claim 30 , wherein said antibody binds specifically to cynomolgus BCMA. 
     
     
         36 . The method of  claim 30 , wherein said antibody comprises a modified Fc part inducing cell death of 20% or more cells of a preparation BCMA expressing cells after 24 hours at a concentration of said antibody of 100 nM by ADCC relative to a control under identical conditions using the same antibody with the parent Fc part as control. 
     
     
         37 . The method of  claim 30 , wherein said antibody is formulated into a pharmaceutical composition comprising a pharmaceutically acceptable excipient. 
     
     
         38 . The method of  claim 33 , wherein said bispecific antibody comprises variable heavy and light chains of an antibody specifically binding to BCMA wherein:
 a. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 17 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 27;   b. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 18 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 28;   c. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 19 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 29;   d. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 20 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 30;   e. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 21 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 31;   f. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 22 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 32;   g. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 23 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 33;   h. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 24 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 34;   i. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 25 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 35; or   j. the variable domain VH comprises the amino acid sequence of SEQ ID NO: 26 and the variable domain VL comprises the amino acid sequence of SEQ ID NO: 36.   
     
     
         39 . The method of  claim 33 , wherein said antibody is formulated into a pharmaceutical composition comprising a pharmaceutically acceptable excipient.