Combination of an anti-edb fibronectin antibody-il-2 fusion protein, and a molecule binding to b cells, b cell progenitors and /or their cancerous counterpart

Abstract

The present invention relates to a combination of an anti-EDb fibronectin antibody-IL-2 fusion protein, and a molecule binding to B cells, B cell progenitors and/or their cancerous counterpart and uses thereof.

1 . A combination comprising at least
 (i) a fusion protein comprising:
 an antibody-part specifically recognising ED b -fibronectin; and 
 an Interleukin-2 part; and 
   (ii) a molecule binding to B cells, B cell progenitors and/or their cancerous counterpart.   
     
     
         2 . A combination according to  claim 1 , wherein the molecule binding to B cells, B cell progenitors and/or their cancerous counterpart is specifically binding to CD20, CD23, CD22, CD40, CD80, HLA-DR or Hu1D10. 
     
     
         3 . A combination according to  claim 2 , wherein the molecule specifically binding to CD20, CD23, CD22, CD40 or CD80 is an antibody or antibody fragment, or a fusion protein thereof. 
     
     
         4 . (canceled) 
     
     
         5 . A combination comprising at least
 (i) a fusion protein comprising:
 an antibody-part specifically recognising EDb-fibronectin; and 
 an Interleukin-2 part; and 
   (ii) a molecule specifically binding to cells expressing CD20.   
     
     
         6 . A combination according to  claim 5 , wherein the molecule specifically binding to cells expressing CD20 is an antibody or antibody fragment specifically binding to CD20. 
     
     
         7 . A combination according to  claim 1 , wherein the antibody-part of (i) recognizes the EDb-domain of fibronectin. 
     
     
         8 . A combination according to  claim 1 , wherein the fusion protein has a fusion protein linker connecting the antibody-part and the Interleukin-2 part. 
     
     
         9 . A combination according to  claim 1 , wherein the antibody-part specifically binds to an ED b  oncofetal fibronectin domain with sub-nanomolar or nanomolar affinity. 
     
     
         10 . A combination according to  claim 1 , wherein the antibody-part contains at least one CDR sequence of the L19 antibody. 
     
     
         11 . A combination according to  claim 1 , wherein the antibody-part comprises the sequences according to SEQ ID no. 6 to 11. 
     
     
         12 . A combination according to  claim 1 , wherein the antibody-part comprises at least one VH chain according to SEQ ID No. 1 or at least one VL chain according to SEQ ID No. 2. 
     
     
         13 . A combination according to  claim 12 , wherein the antibody-part comprises one VH chain according to SEQ ID No. 1 and one VL chain according to SEQ ID No. 2. 
     
     
         14 . A combination according to  claim 12 , wherein the VH chain and the VL chain are connected by an antibody linker. 
     
     
         15 . A combination according to  claim 14 , wherein the antibody linker comprises a sequence according to SEQ ID No. 3, or a sequence having at least 90% identity to the sequence according to SEQ. ID. No. 3. 
     
     
         16 . A combination according to  claim 1 , wherein the Interleukin-2 part is human Interleukin-2 or a functional variant thereof. 
     
     
         17 . A combination according to  claim 16 , wherein the Interleukin-2 part comprises a sequence according to SEQ. ID. No. 4. 
     
     
         18 . (canceled) 
     
     
         19 . A combination according to  claim 8 , wherein the fusion protein linker has a length of 1 to 30 amino acids. 
     
     
         20 . A combination according to  claim 19 , wherein the fusion protein linker comprises a sequence according to SEQ ID No. 5. 
     
     
         21 . A combination according to  claim 3 , wherein the antibody or antibody fragment, or fusion protein thereof is specifically binding to CD20. 
     
     
         22 . A combination according to  claim 21 , wherein the anti-CD20 antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) activity. 
     
     
         23 . A combination according to  claim 6 , wherein the antibody or antibody fragment specifically binding to CD20 is selected from rituximab, Ocrelizumab, PRO131921, Veltuzumab, Ofatumumab, AME-133, and GA-101. 
     
     
         24 . A combination, according  claim 1 , wherein the molecule binding to B cells, B cell progenitors and/or their cancerous counterpart is labelled. 
     
     
         25 . A combination according to  claim 24 , wherein the labelled molecule binding to B cells, B cell progenitors and/or their cancerous counterpart is a radioactively labelled anti-CD20 antibody. 
     
     
         26 . A combination according to  claim 25 , wherein the radioactively labelled anti-CD20 antibody, is selected from a  90 Y-labelled anti-CD20 antibody, an  111 In-labelled anti-CD20 antibody, and an  131 I-labelled anti-CD20 antibody 
     
     
         27 . A combination according to  claim 26 , wherein the radioactively labelled anti-CD20 antibody is selected from Y-90-Ibritumomab-Tiuxetan and I-131 tositumomab. 
     
     
         28 - 33 . (canceled) 
     
     
         34 . A method of treating a subject with cancer, comprising administering a therapeutically effective amount of the combination of  claim 1  to the subject. 
     
     
         35 . The method of  claim 34 , wherein the cancer is lymphoma. 
     
     
         36 . The method of  claim 35 , wherein the lymphoma is a B-cell lymphoma. 
     
     
         37 . The method of  claim 36 , wherein the B-cell lymphoma is a Non-Hodgkin lymphoma. 
     
     
         38 . A method of treating a subject with an autoimmune disease, comprising administering a therapeutically effective amount of the combination of  claim 1  to the subject. 
     
     
         39 . The method of  claim 38 , wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, Crohn's disease, colitis ulcerosa, and autoimmune hemolytic anemia.