Uses of immunoconjugates targeting cd138

Abstract

Disclosed is a method and composition for treating a disease associated with target cells expressing CD138 in a multiple dose regimen. An immunoconjugate comprising an engineered targeting antibody targeting CD138 expressing cells and an effector molecule is administered in a multiple dose regimen. The multiple dose regimen comprises at least two doses and the aggregate dose administered within an active treatment cycle is an aggregate maximum tolerable dose (AMTD) or a fraction of the AMTD. The AMTD and/or said fraction exceeds the dose resulting in dose limiting toxicity (DLT) and/or exceeds the maximum tolerable dose (MTD) when the immunoconjugate is administered as a single dose, including as part of a multiple single dose regimen within said active treatment cycle.

1 . A method for treating a disease associated with target cells expressing CD138 comprising:
 administering to a subject, in particular a human subject, in need thereof an immunoconjugate comprising   at least one engineered targeting antibody targeting CD138 expressing cells, and   at least one effector molecule, wherein said engineered targeting antibody is functionally attached to said effector molecule to form said immunoconjugate,   wherein at least a part of the engineered targeting antibody confers IgG4 isotype properties, wherein   the immunoconjugate is administered in a multiple dose regimen comprising and said administering is performed in a active treatment cycle of at least three weeks at least once a week followed by a resting period of at least one week, wherein the at least three weeks and the at least one week together define a treatment cycle of at least 28 days.   
     
     
         2 . The method of  claim 1 , wherein the immunoconjugate is administered in an active treatment cycle of 21 days. 
     
     
         3 . The method of any one of the preceding claims, wherein the immunoconjugate is administered in equal doses. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein progression free survival or stable disease is maintained during the resting period. 
     
     
         6 . The method of  claim 5 , wherein a level of said immunoconjugate in a body fluid of said subject, during said resting period is at least 0.5 μg/ml, at least 1 μg/ml, at least 2 μg/ml, at least 3 μg/ml, 4 μg/ml, 5 μg/ml or 4.1 g/ml and/or wherein more than 80%, more than 90%, more than 95% of the CD138 of isolated target cells are occupied by said immunoconjugate within four to twenty four hours after completion of administration of the immunoconjugate. 
     
     
         7 . The method of any one of the preceding claims, wherein said effector is a maytansinoid, in particular DM4, and wherein a total amount of maytansinoid administered to said patient within said 21 days is more than 2 mg/m 2 , more than 3 mg/m 2 , more than 4 mg/m 2 , more than 5 mg/m 2 , more than 6 mg/m 2 , more than 7 mg/m 2 , more than 8 mg/m 2 , more than 9 mg/m 2  or more than more than 10 mg/m 2 . 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein after reaching at least
 stable disease, the immunoconjugate is administered as a maintenance therapy less than twice within said active treatment cycle preferably as a repeated single dose of between 60 mg/m 2  and 280 mg/m 2 , including about 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2 , about 100 mg/m 2 , about 110 mg/m 2 , about 120 mg/m 2 , about 130 mg/m 2 , about 140 mg/m 2 , 150 mg/m 2 , about 160 mg/m 2 , about 170 mg/m 2 , about 180 mg/m 2 , about 190 mg/m 2 , about 200 mg/m 2 , about 210 mg/m 2 , about 220 mg/m 2 , about 230 mg/m 2 , about 240 mg/m 2 , about 250 mg/m 2 , about 260 mg/m 2  and about 270 mg/m 2 .   
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the active treatment cycle lasts 21 days and/or the repeated multiple dose consists of 3 equal, preferably equidistant doses, more preferably administered on days 1, 8 and 15. 
     
     
         18 . The method of  claim 17 , wherein said aggregate effective amount is more than 200 mg/m 2 , about 220 mg/m 2 , about 240 mg/m 2 , about 260 mg/m 2 , or about 280 mg/m 2 . 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein said administration is followed, after at least two 21 day treatment cycles, each followed by the 7 day resting period, by a further administration of said the immunoconjugate or pharmaceutical composition as a maintenance therapy. 
     
     
         22 . The method of  claim 21 , wherein the maintenance therapy comprises administering the immunoconjugate or a pharmaceutical composition comprising the same (i) once every three to six weeks or (ii) at repeated multiple doses, wherein each individual dose of immunoconjugate is about 10 mg/m 2 , about 20 mg/m 2 , about 30 mg/m 2 , about 40 mg/m 2 , about 50 mg/m 2 , about 60 mg/m 2 , 70 mg/m 2 , about 80 mg/m 2 , about 90 mg/m 2  or about 100 mg/m 2  lower than the individual dose of a primary therapy and/or wherein individual doses are administered in intervals exceeding the interval of the individual doses, e.g., by 1, 2, 3, 4, 5, 6, 7 days. 
     
     
         23 . A method according to  claim 1 ,
 wherein administration of said immunoconjugate as a multiple dose regime results, 0-2 hours after completion of administration in a mean plasma level of at least 7 μg/ml, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60 or 70 μg/ml.   
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A method according to  claim 1  further comprising administering at least one immunomodulatory agent, including two or three, at least once a week or once in a treatment cycle. 
     
     
         27 . The method of  claim 26 , wherein said immunomodulatory agent is lenalidomide, thalidomide, and/or pomalidomide. 
     
     
         28 . The method of  claim 26  and any following claims, wherein said subject has not previously been exposed to an immunoconjugate comprising an antibody targeting CD138 expressing cells, to lenalidomide, thalidomide, and/or pomalidomide. 
     
     
         29 . The method of  claim 26 , wherein said subject has previously been exposed to an immunoconjugate comprising an antibody targeting CD138 expressing cells, lenalidomide, thalidomide, and/or pomalidomide. 
     
     
         30 . The method of  claim 29 , wherein said subject responded to said exposure to an immunoconjugate comprising an antibody targeting CD138 expressing cells, lenalidomide, thalidomide, and/or pomalidomide. 
     
     
         31 . The method of  claim 30 , wherein said target cells expressing CD138 are refractory to exposure to an immunoconjugate comprising an antibody targeting CD138 expressing cells, lenalidomide, thalidomide, and/or pomalidomide. 
     
     
         32 . The method of  claim 29 , wherein said subject relapsed after said administration. 
     
     
         33 . The method of  claim 26  and any following claims, wherein lenalidomide is administered at a dose of 5 to 35 mg, preferably at about 25 mg, or at a dose of less than 25, 20, 15 or 10 mg, e.g., orally once a day for 21 days and/or wherein dexamethasone is administered at a dose of 20 to 50 mg, preferably at about 40 mg, or at a dose of less than 40 or 30 mg, e.g., orally once a day for 21 days. 
     
     
         34 . The method of any one of the preceding claims, wherein said subject suffers from a solid tumor comprising target cells which express CD138. 
     
     
         35 . The method of  claim 34 , wherein said immunoconjugate is administered in a repeated multiple dose regime with individual doses of 20 mg/m 2  to 160 mg/m 2 . 
     
     
         36 . The method of  claim 34 , wherein said solid tumor is estrogen receptor negative and/or progesterone receptor negative and/or Her2/neu negative. 
     
     
         37 . The method of  claim 34 , wherein the solid tumor is a bladder tumor. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . A kit comprising an antibody against the immunoconjugate according to  claim 1 , and, in a separate container, instructions how to determine, a level of said immunoconjugate in a body fluid obtained from said subject by addition of said antibody to said body fluid. 
     
     
         43 . The method of  claim 1 , wherein the engineered targeting antibody targeting CD138 comprises:
 (a) heavy chain variable region CDR3 comprising amino acid residues 99 to 111 of SEQ ID NO: 1, and   (b) light chain variable region CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 2, respectively.   
     
     
         44 . The method of  claim 43 , wherein the engineered targeting antibody further comprises:
 (a) heavy chain variable region CDR1 and CDR2 comprising amino acid residues 31 to 35 and 51 to 68 of SEQ ID NO: 1, and/or   (b) light chain variable region CDR1 and CDR 2 comprising amino acid residues 24 to 34 and 50 to 56 of SEQ ID NO: 2, respectively.   
     
     
         45 . The method of  claim 44 , wherein the engineered targeting antibody further comprises:
 (a) amino acid residues 123 to 448 of SEQ ID NO: 1, and   (b) amino acid residues 108 to 214 of SEQ ID NO: 2, respectively.