Protein-based pharmaceuticals represent the fastest growing group of drugs in development in the pharmaceutical industry. One of the major challenges in the discovery, development and distribution of biopharmaceuticals is the assessment of changes in their higher-order structure due to chemical modifications. Here, we investigate the interactions of three different biochemical probes (Fabs) generated to detect conformational changes in a therapeutic IgG1 antibody (mAbX) by local hydrogen-deuterium exchange mass spectrometry (HDX-MS). We show that two of the probes target the Fc part of the antibody, while the third probe binds to the hinge region. Through HDX-ETD, we can distinguish specific binding patterns of the Fc-binding probes on mAbX at the single amino acid level. Preliminary surface plasmon resonance (SPR) experiments show that these domain-selective Fab probes are sensitive to conformational changes in distinct regions of a full-length therapeutic antibody upon oxidation.