**1. Introduction**

An in-depth understanding of amino acid sequences and conformations of primary antigens recognized by any monoclonal antibody (mAb) is a necessary prerequisite for clarifying the specificity and functional limitations of a mAb. A protein antigen may be glycosylated or can occur as a monomer or a dimer or a trimer.

In this regard, human leukocyte antigen (HLA) classes are a structurally identical complex family of glycosylated homo- or hetero-dimeric proteins. They are expressed on cell surface complexed with an exogenous or endogenous peptide, as trimers. Defining the monospecificity of mAb raised against one family member of HLA is challenging. Often anti-HLA mAbs are polyreactive in that they bind to sequences common to all family member antigens, which are also known as "public epitopes". It is difficult to identify mAbs binding to unique sequences or private epitopes. Identifying such monospecific mAbs are critical for defining specific functions of antigens. Although sensitive and specific assay protocols are available to define the monospecificity of mAbs, many commercial mAbs, apparently specific for a unique HLA antigen, remain without defining their monospecificity. This review aims to distinguish monospecific mAbs that recognize private epitopes from polyreactive mAbs that bind to public epitopes of one of the HLA class Ib molecules, namely HLA-E, commonly overexpressed on human cancers. A pool of mouse mAbs was developed at Terasaki Foundation Laboratory (TFL) after immunizing with HLA-E. After validating the monospecificity of anti-HLA-E mAbs, their diagnostic and therapeutic potentials have been evaluated. These include (i) immunolocalization of cell surface expression HLA-E on human cancers, (ii) upregulation of CD8+ cytotoxic T lymphocytes, and (iii) restoration of antitumor activity of CD8+ T cells, NKT cells, and NK cells by preventing binding of HLA-E expressed on cancer cells to the inhibitory receptors (CD94/NKG2A) on the immune cells.
