Molecular Genetic Analysis Of Lymphocyte Function

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Our studies of the structural basis by which several pan-anti-MHC-I mAb interact with their MHC-I (HLA-I) antigens form the basis of several engineered forms of the mAb. These are being actively studied with respect to the molecular details of their interactions and the nature of their competitive blocking effects on various NK and myeloid cell receptors. The structural and biochemical studies form the basis of functional studies in humanized mouse models (Panda et al, 2025), and they will be the subject of further humanization and affinity maturation studies. As information accumulates, we expect that these mAb and their derivatives may form the basis of new studies aimed at developing mAb therapies for various tumors. We determined the X-ray structure of four monoclonal antibodies bound to their MHC-I protein antigens and compared these structures to computational models of the complexes calculated by AlphaFold 2 (Boyd et al, 2024). The computational predictions succeeded in the gross assessment of the structures of the Ab and the MHC-I molecules but failed to properly identify the docking sites of the Abs. These X-ray structures of mAb/protein Ag complexes, as demonstrated for a limited set of anti-MHC-I/MHC-I complexes, provide detailed information describing the docking of the Ab to their protein Ags and explain the reactivity and specificity profiles of these Ab. As more mAb/Ag structures are experimentally determined, this should contribute to the elucidation of the parameters that determine mAb structure and Ag recognition as we approach the goal of predicting antigenic specificity from Ab sequence.