Anti-nkg2a antibodies and uses thereof

Abstract

Described herein are anti-NKG2A antibodies suitable for human therapy, including humanized versions of murine anti-NKG2A antibody Z270, as well as related methods and materials for producing and using such antibodies. Exemplary complementarity-determining regions (CDRs) sequences and sites for optional amino acid back-substitutions in framework region (FR) and/or CDRs of such antibodies are also described.

We claim: 
     
         1 . An isolated antibody that specifically binds NKG2A, comprising antigen-binding residues from the complementarity-determining regions (CDRs) of murine antibody Z270 and human acceptor framework sequences, wherein said antibody comprises a VL domain that is at least 90% identical to SEQ ID NO: 4 and a VH domain that is at least 90% identical to SEQ ID NO: 5, and wherein said antibody is more effective than an antibody comprising murine antibody Z270 variable light (VL) (SEQ ID NO: 1) and VH (SEQ ID NO: 2) sequences in potentiating the cytotoxic activity of a CD94/NKG2A-expressing cytotoxic lymphocyte. 
     
     
         2 . The antibody of  claim 1 , comprising a CDR-H1 corresponding to residues 31-35 of SEQ ID NO: 5 and a CDR-H3 corresponding to residues 95-102 of SEQ ID NO: 5, wherein the CDR-H2 comprises residues 50-59 of SEQ ID NO: 5, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         3 . The antibody of  claim 1 , wherein:
 the amino acid at position 5 of the VH domain is V or Q;   the amino acid at position 69 of the VH domain is M or L;   the amino acid at position 71 of the VH domain is T or V;   the amino acid at position 73 of the VH domain is T or K; or   the amino acid at position 75 of the VH domain is T or S, wherein the amino acid numbering is referenced with respect to Kabat numbering.   
     
     
         4 . The antibody of  claim 1 , wherein the VH domain human acceptor framework sequences are free of any back-mutations. 
     
     
         5 . The antibody of  claim 2 , wherein the VH domain comprises the sequence of SEQ ID NO: 5. 
     
     
         6 . The antibody of  claim 5 , comprising a CDR-L1 corresponding to residues 24-34 of SEQ ID NO: 4, a CDR-L2 corresponding to residues 50-56 of SEQ ID NO: 4, and a CDR-L3 corresponding to residues 89-97 of SEQ ID NO: 4, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         7 . The antibody of  claim 6 , wherein the VL domain comprises SEQ ID NO: 4. 
     
     
         8 . The antibody of  claim 1 , which is an IgG4 antibody. 
     
     
         9 . The antibody of  claim 1 , which is an antibody fragment or a multispecific antibody. 
     
     
         10 . The antibody of  claim 1 , wherein the antibody VH domain comprises residues D52, D54, F99, T(100C), and W(100F) from the VH CDRs of murine antibody Z270, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         11 . The antibody of  claim 10 , wherein the antibody VH domain comprises residues N35, Y53, E56, D98, V(100A), and L(100D) from the VH CDRs of murine antibody Z270, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         12 . The antibody of  claim 11 , comprising a CDR-H1 corresponding to residues 31-35 of SEQ ID NO: 5 and a CDR-H3 corresponding to residues 95-102 of SEQ ID NO: 5, wherein the CDR-H2 comprises residues 50-59 of SEQ ID NO: 5, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         13 . The antibody of  claim 1 , comprising a CDR-H1 corresponding to residues 31-35 of SEQ ID NO: 5 and a CDR-H3 corresponding to residues 95-102 of SEQ ID NO: 5, wherein the CDR-H2 comprises residues 50-59 of SEQ ID NO: 5, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         14 . An isolated antibody that specifically binds NKG2A, comprising:
 a CDR-L1 corresponding to residues 24-34 of SEQ ID NO: 4;   a CDR-L2 corresponding to residues 50-56 of SEQ ID NO: 4;   a CDR-L3 corresponding to residues 89-97 of SEQ ID NO: 4;   a CDR-H1 corresponding to residues 31-35 of SEQ ID NO: 5;   a CDR-H3 corresponding to residues 95-102 of SEQ ID NO: 5; and   a CDR-H2 comprising residues 50-59 of SEQ ID NO: 5; and   human acceptor framework sequences;   wherein residues 60-65 in the CDR-H2 are from a VH human acceptor sequence, and   wherein the humanized antibody is more effective than an antibody comprising a variable light (VL) sequence corresponding to SEQ ID NO: 1 and a VH sequences corresponding to SEQ ID NO: 2 in potentiating the cytotoxic activity of a CD94/NKG2A-expressing NK cell, wherein the residue numbering is referenced with respect to Kabat numbering.   
     
     
         15 . The antibody of  claim 14 , which is an IgG4 antibody. 
     
     
         16 . An isolated antibody that specifically binds NKG2A, the antibody comprising a VH domain that comprises non-human CDR residues and human VH acceptor framework sequences, the VH domain comprising a CDR-H1 corresponding to residues 31-35 of SEQ ID NO: 5, a CDR-H2 corresponding to residues 50-65 of SEQ ID NO: 5, and a CDR-H3 corresponding to residues 95-102 of SEQ ID NO: 5, wherein the residue numbering is referenced with respect to Kabat numbering. 
     
     
         17 . The antibody of  claim 16 , which is an IgG4 antibody. 
     
     
         18 . A method for producing an anti-NKG2A antibody, comprising culturing a host cell comprising a nucleic acid encoding the anti-NKG2A antibody of  claim 1  so that the nucleic acid is expressed and the antibody produced. 
     
     
         19 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of treating a human patient suffering from a disorder selected from a cancer, a viral disease, an inflammatory disorder, and an autoimmune disorder, comprising administering the pharmaceutical composition of  claim 19 .