Abstract Antigen presentation on MHC Class II (pMHCII presentation) plays an essential role in the adaptive immune response to extracellular pathogens and cancerous cells. But it can also reduce the efficacy of large-molecule drugs by triggering an anti-drug response. Significant progress has been made in pMHCII presentation modeling due to the collection of large-scale pMHC mass spectrometry datasets (ligandomes) and advances in deep machine learning. Here, we develop graph-pMHC, a graph neural network approach to predict pMHCII presentation. We derive adjacency matrices for pMHCII using Alphafold2-multimer, and address the peptide-MHC binding groove alignment problem with a simple graph enumeration strategy. We demonstrate that graph-pMHC dramatically outperforms methods with suboptimal inductive biases, such as the multilayer-perceptron-based NetMHCIIan-4.0 (+22.84% average precision). Finally, we create an antibody drug immunogenicity dataset from clinical trial data, and develop a method for measuring anti-antibody immunogenicity risk using pMHCII presentation models. In comparison with BioPhi’s Sapiens score, a deep learning based measure of the humanness of an antibody drug, our strategy achieves a 7.14% ROC AUC improvement in predicting antibody drug immunogenicity.

Graph-pMHC: Graph Neural Network Approach to MHC Class II Peptide Presentation and Antibody Immunogenicity