Combining cd27 agonists and immune checkpoint inhibition for immune stimulation

Abstract

The present invention relates to treatments of conditions ameliorated by stimulation of an immune response, in particular by the stimulation of antigen-specific T-lymphocytes. Treatment of such conditions according to the invention is effected by the combination of an anti-human CD27 agonistic antibody together with a number of immune checkpoint inhibitors.

What is claimed is: 
     
         1 . An anti-human CD27 agonistic antibody, such as hCD27.15 or 1F5, or an antibody analogue thereof, for use in the treatment of a condition ameliorated by stimulation of an immune response, in particular stimulation of antigen-specific T-lymphocytes, wherein in said treatment a number of immune checkpoint protein inhibitors is administered. 
     
     
         2 . An anti-human CD27 agonistic antibody according to  claim 1 , wherein an immune checkpoint protein inhibitor is selected from an inhibitor of CTLA-4, PD1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3 or KIR. 
     
     
         3 . An anti-human CD27 agonistic antibody according to  claim 1 , wherein the condition ameliorated by immune stimulation, in particular stimulation of antigen-specific T-lymphocytes is selected from infectious diseases, such as bacterial, fungal, viral and parasitic infectious diseases, immunization against a pathogen, such as a pathogen selected from bacteria, fungi, viruses or parasites, or vaccination against toxins, or self-antigens, including antigens expressed on benign or malignant tumors, such as cancers, or conditions associated with uncontrolled proliferation of cells such as cancers. 
     
     
         4 . An anti-human CD27 agonistic antibody according to  claim 1 , wherein the treatment is vaccination and a vaccine is administered in the treatment. 
     
     
         5 . Immune checkpoint inhibitor for use in the treatment of a condition ameliorated by stimulation of an immune response, in particular stimulation of antigen-specific T-lymphocytes, wherein in said treatment an anti-human CD27 agonistic antibody, such as hCD27.15 or 1F5, or an antibody analogue thereof, is administered. 
     
     
         6 . Immune checkpoint inhibitor according to  claim 5 , wherein the immune checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3 or KIR. 
     
     
         7 . Immune checkpoint inhibitor according to  claim 5 , wherein the condition ameliorated by immune stimulation is selected from infectious diseases, such as bacterial, fungal, viral and parasitic infectious diseases, immunization against a pathogen, such as a pathogen selected from bacteria, fungi, viruses or parasites, or vaccination against toxins, or self-antigens, including antigens expressed on benign or malignant tumors, such as cancers, or conditions associated with uncontrolled proliferation of cells such as cancers. 
     
     
         8 . An immune checkpoint inhibitor according to  claim 5 , wherein the treatment is vaccination and wherein a vaccine is administered in the treatment. 
     
     
         9 . Combination of an anti-human CD27 agonistic antibody, such as hCD27.15 or 1F5, or an antibody analogue thereof, together with a number of immune checkpoint inhibitors for use in the treatment of a condition ameliorated by stimulation of an immune response, particularly stimulation of antigen-specific T-lymphocytes. 
     
     
         10 . Combination according to  claim 9 , wherein an immune checkpoint inhibitor is selected from an inhibitor of CTLA-4, PD1, PD-L1, PD-L2, LAG-3, BTLA, B7H3, B7H4, TIM3 or KIR. 
     
     
         11 . Combination according to  claim 9 , wherein the condition ameliorated by immune stimulation is selected from infectious diseases, such as bacterial, fungal, viral and parasitic infectious diseases, immunization against a pathogen, such as a pathogen selected from bacteria, fungi, viruses or parasites, or vaccination against toxins, or self-antigens, including antigens expressed on benign or malignant tumors, such as cancers, or conditions associated with uncontrolled proliferation of cells such as cancers. 
     
     
         12 . Combination according to  claim 9 , wherein the treatment is vaccination and wherein a vaccine is administered in the treatment. 
     
     
         13 . A method of treating a condition ameliorated by stimulation of an immune response, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-human CD27 agonistic antibody and further an immune checkpoint protein inhibitor. 
     
     
         14 . The method of  claim 13 , wherein said anti-human CD27 agonistic antibody is selected from the group consisting of: an anti-human CD27 agonistic antibody comprising the CDR amino acid sequences of SEQ ID NO: 1, 2, 3, 4, 5, 6, or a variant sequence; a humanized analogue of antibody hCD27.15; an analogue of antibody hCD27.15 that binds to the same epitope as hCD27.15; antibody 1F5; an anti-human CD27 agonistic antibody that does not require cross-linking. 
     
     
         15 . The method of  claim 13 , wherein said further immune checkpoint inhibitor protein is selected from the group consisting of: an CTLA-4 antibody, an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti LAG-3 antibody, an anti-BTLA antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-TIM3 antibody and an anti-MR antibody. 
     
     
         16 . The method of  claim 13 , wherein said further immune checkpoint inhibitor protein is an anti-PD1 antibody. 
     
     
         17 . The method of  claim 13 , wherein said anti-PD-1 antibody is pembrolizumab. 
     
     
         18 . The method of  claim 13 , wherein said anti-PD-1 antibody is nivolumab. 
     
     
         19 . The method of  claim 13 , wherein said further immune checkpoint inhibitor protein is an anti-LAG3 antibody. 
     
     
         20 . The method of  claim 19 , wherein said anti-LAG3 antibody comprises the heavy chain and light chain amino acid sequences of SEQ ID NO: 23 and SEQ ID NO: 24, respectively. 
     
     
         21 . The method of  claim 13 , wherein the subject in need of treatment suffers from cancer. 
     
     
         22 . The method of  claim 13 , wherein the subject in need of treatment suffers from an infection (such as a bacterial, fungal, viral and parasitic infectious diseases). 
     
     
         23 . A vaccine comprising an anti-human CD27 agonistic antibody and further comprising an immune checkpoint protein inhibitor. 
     
     
         24 . The vaccine of  claim 23 , wherein said further immune checkpoint protein inhibitor is selected from the group consisting of: an CTLA-4 antibody, an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti LAG-3 antibody, an anti-BTLA antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-TIM3 antibody and an anti-MR antibody. 
     
     
         25 . The vaccine of  claim 23 , wherein said further immune checkpoint inhibitor protein is an anti-PD1 antibody. 
     
     
         26 . The vaccine of  claim 23 , wherein said anti-PD-1 antibody is pembrolizumab. 
     
     
         27 . The vaccine of  claim 23 , wherein said anti-PD-1 antibody is nivolumab. 
     
     
         28 . The vaccine of  claim 23 , wherein said further immune checkpoint inhibitor protein is an anti-LAG3 antibody. 
     
     
         29 . The vaccine of  claim 23 , wherein said anti-LAG3 antibody comprises the heavy chain and light chain amino acid sequences of SEQ ID NO:23 and SEQ ID NO:24, respectively.