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bioRxiv Preprint

In the last two decades, ample of methods have been developed to predict the classical HLA binders in an antigen. In contrast, limited attempts have been made to develop methods for predicting binders for non-classical HLA; due to the scarcity of sufficient experimental data and lack of community interest. Of Note, non-classical HLA plays a crucial immunomodulatory role and regulates various immune responses. Recent studies revealed that non-classical HLA (HLA-E & HLA-G) based immunotherapies have many advantages over classical HLA based-immunotherapy, particularly against COVID-19. In order to facilitate the scientific community, we have developed an artificial intelligence-based method for predicting binders of non-classical HLA alleles (HLA-G and HLA-E). All the models were trained and tested on experimentally validated data obtained from the recent release of IEDB. The machine learning based-models achieved more than 0.98 AUC for HLA-G alleles on validation or independent dataset. Similarly, our models achieved the highest AUC of 0.96 and 0.88 on the validation dataset for HLA-E*01:01, HLA-E*01:03, respectively. We have summarized the models developed in the past for non-classical HLA binders and compared with the models developed in this study. Moreover, we have also predicted the non-classical HLA binders in the spike protein of different variants of virus causing COVID-19 including omicron (B.1.1.529) to facilitate the community. One of the major challenges in the field of immunotherapy is to identify the promiscuous binders or antigenic regions that can bind to a large number of HLA alleles. In order to predict the promiscuous binders for the non-classical HLA alleles, we developed a web server HLAncPred (, and a standalone package.

Dhall, A.; Patiyal, S.; Raghava, G. P. S.