Targeting the NKG2A axis with a TCR mimic antibody containing an active Fc domain promotes anti-tumor immunity

Abstract

Abstract The NKG2A axis is an emerging immune checkpoint. Blocking antibodies to the NKG2A receptor in combination with cancer vaccines and PD-(L)1 antibodies have been found to enhance anti-tumor immunity in murine models and cancer patients. The ligand for the NKG2A receptor is the non-classical major histocompatibility (MHC) class Ib molecule, Qa-1 bin mice (HLA-E in humans), loaded with leader peptides from classical MHC class Ia molecules to form Qa-1 b/Qdm peptide complexes. Here, we explore the therapeutic value of targeting the NKG2A ligand, not done previously, using our recently described single-domain T-cell receptor mimic (TCRm) antibody, EXX-1. Two syngeneic murine tumor models (A20 and CT26) were used to evaluate the therapeutic potential of EXX-1 and its mode(s) of action. The initial study done showed EXX-1 Fc active (mIgG2a) displayed optimal tumor growth inhibition and prolonged survival time in mice compared to a modified form of EXX-1 containing an inactive Fc domain. These findings suggested that in addition to blocking the NKG2A pathway, EXX-1 Fc active antibody likely induces tumor cell death via antibody dependent cellular cytotoxicity (ADCC). Moreover, mice treated with EXX-1 antibody as single agent therapy showed significantly better survival outcomes compared to the cohort of mice treated with blocking antibody to the NKG2A receptor. This implies that there might be potential benefits of targeting the NKG2a ligand over the NKG2A receptor though this will require further investigation. Additionally, combination therapy using EXX-1 Fc active and PD-(L)1 blocking antibodies revealed markedly improved rates of tumor-free mice compared to mice receiving treatment with EXX-1 Fc active or anti-PD-(L)1 antibody alone.