Use of an active substance binding to CD28 for producing a pharmaceutical composition for the treatment of B-CLL

Abstract

The invention relates to the use of a superagonistic monoclonal antibody (mAb), which is specific for a naturally costimulatory receptor expressed on T cells, or a mimicry compound thereto, for producing a pharmaceutical composition for the treatment of diseases occurring with lacking costimulability of T cells, in particular of the B-CLL.

1 . A pharmaceutical composition for the treatment of diseases lacking costimulation of T cells comprising an active substance comprising a superagonistic monoclonal antibody (mAb), which is specific for a naturally costimulatory receptor expressed on T cells or a mimicry compound thereto.  
     
     
         2 . The composition according to  claim 1 , wherein the disease is a disease from the group comprising chronic lymphocytic leukemia of the B-cell type (B-CLL), agammaglobulinemia, selective immunoglobulin deficiencies comprising selective IgA deficiency, common variable immunodeficiencies (CVID), diseases where compared to solid tumors comprising lung carcinoma, the capability of tumor-specific T cells is limited, because of the lack of expression of costimulatory ligands on tumor cells.  
     
     
         3 . The composition of  claim 1 , wherein the mAb is obtainable from a non-human mammal immunized with the naturally costimulatory receptor or a partial sequence thereof, wherein cells are taken from the non-human mammal and hybridoma cells are produced, and wherein the thus obtained hybridoma cells are selected such that there are contained mAb's which superagonistically bind to the receptor.  
     
     
         4 . The composition according to  claim 1 , wherein the mimicry compound can be identified in a screening method, wherein a prospective mimicry compound or mixtures of prospective mimicry compounds are subjected to a binding assay with the naturally costimulatory receptor or to a partial sequence thereof, and wherein active substances binding to the receptor or to the partial sequence thereof are selected, if applicable followed by an assay for testing for superagonistic stimulation of several to all sub-groups of the T lymphocytes.  
     
     
         5 . The composition according to  claim 1 , wherein the mAb can be obtained from hybridoma cells, as filed under the DSM numbers DSM ACC2531 (mAb: 9D7 or 9D7G3H11) or DSM ACC2530 (mAb: 5.11A or 5.11A1C2H3), or 
 wherein the antibody in the heavy chain contains an amino acid sequence for the variable region according to SEQ ID NO: 19 (VHC) and in the light chain an amino acid sequence for the variable region according to SEQ ID NO: 25 (VLC).    
     
     
         6 . The composition according to  claim 1 , wherein the active substance comprises a superagonistic monoclonal antibody containing one or several sequences of SEQ ID NOS: 9, 11, 13 or 15, or one or several sequences of SEQ ID NOS: 10, 12, 14 or 16, or one or several sequences of SEQ ID NOS: 18 or 19, or sequences homologous thereto.  
     
     
         7 . A method for the treatment of diseases lacking costimulation of T cells, wherein either: 
 to a patient is administered a pharmaceutical composition comprising a superagonistic monoclonal antibody specific for a naturally costimulatory receptor on T cells or a mimicking compound thereto and galenically prepared for a defined dosage form comprising IV injection; or    from a patient is taken a body liquid comprising blood, further comprising T lymphocytes or forerunner cells thereto, the body liquid is reacted with a superagonistic monoclonal antibody specific for a naturally costimulatory receptor on T cells or a mimicking compound thereto, and the thus treated body liquid is administered again to the patient in a defined dosage form comprising IV injection.    
     
     
         8 . A method for reducing B-CLL B cells and expanding T cells in a liquid containing normal T cells, B cells and B-CLL B cells, wherein by interaction of the normal T cells present in the liquid with a superagonistic mAb specific for a naturally costimulatory receptor on resting T cells or a mimicry compound thereto, the normal T cells are activated or expanded, 
 wherein by interaction of the B-CLL T cells present in the liquid with the superagonistic mAb specific for a naturally costimulatory receptor on resting T cells or the mimicry compound thereto, the B-CLL cells are activated in a CD40 ligand or expanded,    wherein the activated or expanded B-CLL T cells carrying CD40 ligands induce the expression of one or both CD86 or CD80 in B-CLL B cells carrying CD40, and    wherein autologous tumor-specific T cells are costimulatorily activated or expanded by the B-CLL B cells carrying CD86 or CD80, and    wherein the activated tumor-specific T cells eliminate the B-CLL B cells.    
     
     
         9 . The composition of  claim 2 , wherein the expression of costimulatory ligands on tumor cells causes the T cells to cytotoxically react against the tumor cells and wherein T cells are made capable of cytotoxically reacting by superagonistic CD28 stimulation.  
     
     
         10 . The composition of  claim 5 , wherein the heavy and light chains contain the amino sequences of SEQ ID NO: 24 for the constant region of the heavy chain (CHC) and the amino sequence of SEQ ID NO: 21 for the constant region of the light chain (CHC).  
     
     
         11 . The composition of  claim 5 , wherein the heavy chain and the light chain contain the amino acid sequences of SEQ ID NO: 20 for the leader peptide.  
     
     
         12 . The composition of  claim 5 , wherein the heavy chain and the light chain each consist of the full length sequences of SEQ ID NO: 28 and SEQ ID NO: 27 respectively, wherein the C terminus comprises the variants of SEQ ID NOS: 22, 23 and 24.