DEFINING THE BIOCHEMICAL AND BIOPHYSICAL CHARACTERISTICS OF ANTI-HLA-C*07:02 ALLOANTIBODIES IN SOLID ORGAN TRANSPLANTATION

Abstract

Antibody-mediated rejection remains a threat to long-term graft survival in organ transplantation. However, some patients with circulating antibodies do not experience rejection suggesting not all antibodies are pathogenic. Stratification of high-risk patients remains a challenge due to our inability to distinguish the presence of pathogenic antibodies. A Human alloantibody repertoire isolated from a Human phage-FAB library was thoroughly characterized to investigate the influence of antigen density, antibody binding kinetics, and structural interactions on their relative pathogenicity. The level of antigen density was shown to be directly associated with pathogenicity in our study. Kinetics, such as affinity and off-rate may not be a primary predictor of antibody pathogenicity. The binding of pathogenic antibodies caused an overall increase in structural stability to the HLA-antibody complex, according to structural interactions assessed using HDX-MS. These findings have significant implications for our knowledge of the biologic determinants of pathogenic alloantibodies.