Combination il-2 immunoconjugate therapy

Abstract

The present invention provides combinations of (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, and (b) a second antibody engineered to have increased effector function, for use in treating a disease in an individual in need thereof. Further provided are pharmaceutical compositions comprising the combinations, and methods of using them.

1 . A combination of (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, and (b) a second antibody engineered to have increased effector function, for use in treating a disease in an individual in need thereof. 
     
     
         2 . The combination of  claim 1 , wherein the effector moiety is a cytokine 
     
     
         3 . The combination of  claim 1  or  2 , wherein the effector moiety is a cytokine selected from the group consisting of IL-2, GM-CSF, IFN-α, and IL-12. 
     
     
         4 . The combination of any one of  claims 1  to  3 , wherein the effector moiety is IL-2. 
     
     
         5 . The combination of  claim 4 , wherein the IL-2 effector moiety is a mutant IL-2 effector moiety comprising at least one amino acid mutation, particularly an amino acid substitution, that reduces or abolishes the affinity of the mutant IL-2 effector moiety to the a-subunit of the IL-2 receptor but preserves the affinity of the mutant IL-2 effector moiety to the intermediate-affinity IL-2 receptor, compared to the non-mutated IL-2 effector moiety. 
     
     
         6 . The combination of any one of  claims 1  to  5 , wherein the first antibody is a full-length antibody, particularly an IgG class antibody, more particularly and IgG 1  sub-class antibody. 
     
     
         7 . The combination of any one of  claims 1  to  6 , wherein the effector moiety shares an amino-or carboxy-terminal peptide bond with the first antibody. 
     
     
         8 . The combination of any one of  claims 1  to  7 , wherein the first antibody is engineered to have reduced binding to an activating Fc receptor, particularly reduced binding to human FcγRIIIa. 
     
     
         9 . The combination of any one of  claims 1  to  8 , wherein the first antibody comprises an amino acid substitution at position P329 of the immunoglobulin heavy chains (Kabat numbering). 
     
     
         10 . The combination of any one of  claims 1  to  9 , wherein the first antibody comprises the amino acid substitutions L234A, L235A and P329G in the immunoglobulin heavy chains. 
     
     
         11 . The combination of any one of  claims 1  to  10 , wherein the immunoconjugate essentially consists of an effector moiety, particularly a single chain effector moiety, and a first antibody engineered to have reduced effector function, wherein the effector moiety is fused at its amino-terminal amino acid to the carboxy-terminus of one of the heavy chains of the first antibody, optionally through a peptide linker. 
     
     
         12 . The combination of any one of  claims 1  to  11 , wherein the first antibody is directed to an antigen presented on a tumor cell or in a tumor cell environment. 
     
     
         13 . The combination of any one of  claims 1  to  12 , wherein the second antibody is a full-length IgG class antibody, particularly an IgG 1  subclass antibody. 
     
     
         14 . The combination of any one of  claims 1  to  13 , wherein the effector function is selected from the group of binding to an activating Fc receptor, ADCC, ADCP, CDC, and cytokine secretion. 
     
     
         15 . The combination of any one of  claims 1  to  14 , wherein the effector function is increased binding to an activating Fc receptor and/or increased ADCC. 
     
     
         16 . The combination of any one of  claims 1  to  15 , wherein the second antibody is engineered by introduction of one or more amino acid mutations in the Fc region or by modification of the glycosylation in the Fc region. 
     
     
         17 . The combination of any one of  claims 1  to  16 , wherein the second antibody is engineered to have an increased proportion of non-fucosylated oligosaccharides in the Fc region as compared to a non-engineered antibody. 
     
     
         18 . The combination of any one of  claims 1  to  17 , wherein the second antibody is directed to an antigen presented on a tumor cell. 
     
     
         19 . The combination of any one of  claims 1  to  18 , wherein the disease is a disorder treatable by stimulation of effector cell function, particularly cancer. 
     
     
         20 . The combination of any one of  claims 1  to  19 , wherein the individual is a mammal, particularly a human. 
     
     
         21 . A pharmaceutical composition comprising (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, and (b) a second antibody engineered to have increased effector function, in a pharmaceutically acceptable carrier. 
     
     
         22 . A method of treating a disease in an individual, comprising administering to the individual a combination of (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, and (b) a second antibody engineered to have increased effector function, in a therapeutically effective amount. 
     
     
         23 . A method of stimulating effector cell function in an individual, comprising administering to the individual a combination of (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, and (b) a second antibody engineered to have increased effector function, in an amount effective to stimulate effector cell function. 
     
     
         24 . A kit intended for the treatment of a disease, comprising in the same or in separate containers (a) an immunoconjugate comprising a first antibody engineered to have reduced effector function and an effector moiety, (b) a second antibody engineered to have increased effector function, and (c) optionally a package insert comprising printed instructions directing the use of the combined treatment as a method for treating the disease.