Means and Methods for Treating Tumorous Diseases

Abstract

Provided are pharmaceutical means and methods for the prevention, treatment or amelioration of indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) and B cell leukemia comprising the administration of a bispecific single chain antibody construct to a subject in the need thereof and the use of said bispecific single chain antibody construct for the preparation of a pharmaceutical composition for the prevention, treatment or amelioration of indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) and B cell leukemia, whereby said construct is to be administered for at least 1 week in specified daily doses. Moreover, the invention relates to kits comprising a bispecific single chain antibody construct to be used in accordance with this invention.

1 - 21 . (canceled) 
     
     
         22 . A method for treating or ameliorating relapse and/or recurrence of indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) or relapse and/or recurrence of B cell leukemia in a subject suffering from relapsed and/or recurrent B NHL and/or B cell leukemia, the method comprising administering to the subject
 (a) a pharmaceutical composition comprising a bispecific single chain antibody comprising the amino acid sequence set forth in SEQ ID NO: 2; and   (b) a chemotherapy, a radiation therapy, a hormonal therapy, and/or a biological or immunotherapy,   
       wherein the bispecific single chain antibody is administered in a daily dose over at least six hours by continuous intravenous infusion for at least four weeks, wherein a lower daily dose of less than 10 μg to 80 μg per square meter subject body surface area of the bispecific single chain antibody is administered as an initial dose followed by a higher maintenance daily dose. 
     
     
         23 . The method of  claim 22 , wherein the initial dose is between 0.5-5 μg per square meter subject body surface area per 24 hours and the maintenance daily dose is 15 μg per square meter subject body surface area per 24 hours. 
     
     
         24 . The method of  claim 22 , wherein the initial dose is 15 μg per square meter subject body surface area and the maintenance daily dose is 45 μg per square meter subject body surface area. 
     
     
         25 . The method of  claim 22 , wherein the initial dose is 5 μg per square meter subject body surface area per 24 hours and the maintenance daily dose is further increased to 45 μg per square meter subject body surface area per 24 hours for the remaining period of the treatment. 
     
     
         26 . The method of  claim 22 , wherein the bispecific single chain antibody is administered in a daily dose by continuous intravenous infusion for at least eight weeks. 
     
     
         27 . The method of  claim 22 , wherein the bispecific single chain antibody is administered in a daily dose by continuous intravenous infusion for at least twelve weeks. 
     
     
         28 . The method of  claim 22 , further comprising an infusion-free period following the treatment. 
     
     
         29 . The method of  claim 28 , wherein the infusion-free period is about four weeks. 
     
     
         30 . The method of  claim 28 , wherein the subject receives several rounds of treatment followed by an infusion-free period following each round of treatment. 
     
     
         31 . A method for treating or ameliorating indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) or B cell leukemia in a subject, the method comprising administering to the subject
 (a) a pharmaceutical composition comprising a bispecific single chain antibody; and   (b) a chemotherapy, a radiation therapy, a hormonal therapy, and/or a biological or immunotherapy,   wherein the bispecific single chain antibody construct comprises binding domains specific for human CD3 and human CD19, wherein the corresponding variable heavy chain regions (VH) and the corresponding variable light chain regions (VL) regions are arranged, from N-terminus to C-terminus, in the order,   VL(CD19)-VH(CD19)-VH(CD3)-VL(CD3),   VH(CD19)-VL(CD19)-VH(CD3)-VL(CD3),   VH(CD3)-VL(CD3)-VH(CD19)-VL(CD19) or   VH(CD3)-VL(CD3)-VL(CD19)-VH(CD19),   wherein the bispecific single chain antibody construct is administered for at least 1 week in a daily dose of 10 μg to 80 μg per square meter subject body surface area and wherein the daily dose is administered over at least 6 hours, and   wherein each VL and VH region comprises a CDR1, CDR2, and CDR3 region.   
     
     
         32 . The method of  claim 31 , wherein the daily dose is administered over at least 10 hours. 
     
     
         33 . The method of  claim 31 , wherein the daily dose is administered over at least 12 hours. 
     
     
         34 . The method of  claim 31 , wherein the daily doses is administered over 24 hours. 
     
     
         35 . The method of  claim 31 , wherein the VH and VL regions of the CD3 specific domain are from a CD3 specific antibody selected from the group consisting of: OKT-3, X35-3, VIT3, BMA030 (BW264/56), CLB-T3/3, CRIS7, YTH12.5, F111-409, TR-66, WT31, WT32, SPv-T3b, 11D8, XIII-141, XIII-46, XIII-87, 12F6, T3/RW2-8C8, T3/RW2-4B6, OKT3D, M-T301, SMC2 and F101.01. 
     
     
         36 . The method of  claim 31 , wherein the VH region of the CD3 specific domain comprises at least one CDR3 region comprising the amino acid sequence: SEQ ID NO: 11. 
     
     
         37 . The method of  claim 31 , wherein the VH region of the CD3 specific domain comprises at least one CDR2 region comprising the amino acid sequence: SEQ ID NO: 10. 
     
     
         38 . The method of  claim 31 , wherein the VH region of the CD3 specific domain comprises at least one CDR1 region comprising the amino acid sequence: SEQ ID NO: 9. 
     
     
         39 . The method of  claim 31 , wherein the VL region of the CD3 specific domain comprises at least one CDR3 region comprising the amino acid sequence: SEQ ID NO: 14. 
     
     
         40 . The method of  claim 31 , wherein the VL region of the CD3 specific domain comprises at least one CDR2 region comprising the amino acid sequence: SEQ ID NO: 13. 
     
     
         41 . The method of  claim 31 , wherein the VL region of the CD3 specific domain comprises at least one CDR1 region comprising the amino acid sequence: SEQ ID NO: 12. 
     
     
         42 . The method of  claim 31 , wherein the VH region of the CD3 specific domain comprises SEQ ID NO: 17, the VH region of the CD19 specific domain comprises SEQ ID NO: 15, the VL region of the CD3 specific domain comprises SEQ ID NO: 18 and/or the VL region of the CD19 specific domain comprises SEQ ID NO: 16. 
     
     
         43 . The method of  claim 31 , wherein the bispecific single chain antibody construct comprises an amino acid sequence selected from the group consisting of
 (a) an amino acid sequence set forth in SEQ ID NO: 2, 4, 6, or 8;   (b) an amino acid sequence encoded by a nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, or 7; and   (c) an amino acid sequence encoded by a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, or 7,   wherein the amino acid sequence is capable of specifically binding to CD3 and CD19.   
     
     
         44 . The method of  claim 31 , wherein the variable domains are connected by additional linker sequences. 
     
     
         45 . The method of  claim 31 , wherein the daily administration is continued for at least 2 weeks, at least 3 weeks, or at least 4 weeks. 
     
     
         46 . The method of  claim 31 , wherein the pharmaceutical composition is administered in combination with one or more further pharmaceutical agents. 
     
     
         47 . The method of  claim 31 , wherein the subject is a human patient. 
     
     
         48 . The method of  claim 31 , wherein the bispecific single chain antibody construct is administered in a daily dose of less than 10 μg to 80 μg per square meter subject body surface area on the first day. 
     
     
         49 . The method of  claim 31 , wherein the initial dose is between 0.5-5 μg per square meter subject body surface area per 24 hours and the maintenance daily dose is 15 pg per square meter subject body surface area per 24 hours. 
     
     
         50 . The method of  claim 31 , wherein the initial dose is 15 μg per square meter subject body surface area and the maintenance daily dose is 45 μg per square meter subject body surface area. 
     
     
         51 . The method of  claim 31 , wherein the initial dose is 5 μg per square meter subject body surface area per 24 hours and the maintenance daily dose is further increased to 45 μg per square meter subject body surface area per 24 hours for the remaining period of the treatment. 
     
     
         52 . The method of  claim 31 , wherein the bispecific single chain antibody is administered in a daily dose by continuous intravenous infusion for at least eight weeks. 
     
     
         53 . The method of  claim 31 , wherein the bispecific single chain antibody is administered in a daily dose by continuous intravenous infusion for at least twelve weeks. 
     
     
         54 . The method of  claim 31 , further comprising an infusion-free period following the treatment. 
     
     
         55 . The method of  claim 31 , wherein the infusion-free period is about four weeks. 
     
     
         56 . The method of  claim 31 , wherein the subject receives several rounds of treatment followed by an infusion-free period following each round of treatment. 
     
     
         57 . A method for treating or ameliorating relapse and/or recurrence of indolent or aggressive B cell non-Hodgkin lymphoma (B NHL) or relapse and/or recurrence of B cell leukemia in a subject suffering from relapsed and/or recurrent B NHL and/or B cell leukemia, the method comprising administering to the subject a pharmaceutical composition comprising a bispecific single chain antibody comprising the amino acid sequence set forth in SEQ ID NO: 2; wherein the bispecific single chain antibody is administered in a daily dose over at least six hours by continuous intravenous infusion for at least four weeks, wherein a lower daily dose of less than 10 μg to 80 μg per square meter subject body surface area of the bispecific single chain antibody is administered as an initial dose followed by a higher maintenance daily dose, and wherein the infusion is followed by an infusion-free period. 
     
     
         58 . The method of  claim 57 , wherein the infusion-free period is about four weeks. 
     
     
         59 . The method of  claim 57 , wherein the subject receives several rounds of treatment followed by an infusion-free period following each round of treatment.