Novel immunoconjugates

Abstract

The present invention generally relates to antigen-specific immunoconjugates for selectively delivering effector moieties that influence cellular activity. More specifically, the invention provides novel immunoconjugates comprising a first antigen binding moiety, an Fc domain and a single effector moiety. In addition, the present invention relates to polynucleotides encoding such immunoconjugates, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the immunoconjugates of the invention, and to methods of using these immunoconjugates in the treatment of disease.

1 . An immunoconjugate comprising a first antigen binding moiety, an Fc domain consisting of two subunits, and an effector moiety, wherein not more than one effector moiety is present. 
     
     
         2 . The immunoconjugate of  claim 1 , wherein said Fc domain comprises a modification promoting heterodimerization of two non-identical polypeptide chains. 
     
     
         3 . The immunoconjugate of  claim 2 , wherein said modification is a knob-into-hole modification, comprising a knob modification in one of the subunits of the Fc domain and a hole modification in the other one of the two subunits of the Fc domain. 
     
     
         4 . The immunoconjugate of  claim 1 , wherein said Fc domain is engineered to have altered binding to an Fc receptor and/or altered effector function. 
     
     
         5 . The immunoconjugate of  claim 1 , wherein the effector moiety is a cytokine. 
     
     
         6 . The immunoconjugate of  claim 5 , wherein said cytokine is IL-2. 
     
     
         7 . An isolated polynucleotide encoding the immunoconjugate of  claim 1  or a fragment thereof. 
     
     
         8 . An expression vector comprising the isolated polynucleotide of  claim 7 . 
     
     
         9 . A host cell comprising the expression vector of  claim 8 . 
     
     
         10 . A method of producing the immunoconjugate comprising a first antigen binding moiety, an Fc domain consisting of two subunits, and an effector moiety, wherein not more than one effector moiety is present, comprising culturing the host cell of  claim 9  under conditions suitable for the expression of the immunoconjugate and optionally recovering the immunoconjugate. 
     
     
         11 . A pharmaceutical composition comprising the immunoconjugate of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . A method of treating a disease in an individual, comprising administering to said individual a therapeutically effective amount of a composition comprising the immunoconjugate of  claim 1  in a pharmaceutically acceptable form. 
     
     
         13 . A conjugate comprising a first Fab molecule which does not specifically bind to any antigen, an Fc domain consisting of two subunits, and an effector moiety, wherein not more than one effector moiety is present. 
     
     
         14 . The conjugate of  claim 13 , wherein said effector moiety is fused to the amino- or carboxy-terminal amino acid of one of said two subunits of the Fc domain, optionally through a linker peptide. 
     
     
         15 . The conjugate of  claim 13 , wherein said first Fab molecule is fused to the amino-terminal amino acid of one of said two subunits of the Fc domain, optionally through a linker peptide or an immunoglobulin hinge region. 
     
     
         16 . The conjugate of  claim 13 , wherein said Fc domain is engineered to have altered binding to an Fc receptor and/or altered effector function. 
     
     
         17 . The conjugate of  claim 13 , wherein the conjugate comprises a first and a second Fab molecule. 
     
     
         18 . The conjugate of  claim 17 , wherein said first and said second Fab molecule and said Fe domain are part of an immunoglobulin molecule. 
     
     
         19 . The conjugate of  claim 18 , wherein said effector moiety is fused to the carboxy-terminal amino acid of one of the immunoglobulin heavy chains, optionally through a linker peptide. 
     
     
         20 . The conjugate of  claim 13 , wherein the effector moiety is a cytokine. 
     
     
         21 . An isolated polynucleotide encoding the conjugate of  claim 13  or a fragment thereof. 
     
     
         22 . An expression vector comprising the isolated polynucleotide of  claim 21 . 
     
     
         23 . A host cell comprising the expression vector of  claim 21 . 
     
     
         24 . A method of producing the conjugate comprising a first Fab molecule which does not specifically bind to any antigen, an Fc domain consisting of two subunits, and an effector moiety, wherein not more than one effector moiety is present, comprising culturing the host cell of  claim 23  under conditions suitable for the expression of the conjugate and optionally recovering the conjugate. 
     
     
         25 . A pharmaceutical composition comprising the conjugate of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
         26 . A method of treating a disease in an individual, comprising administering to said individual a therapeutically effective amount of a composition comprising the conjugate of  claim 13  in a pharmaceutically acceptable form.