ABSTRACT
Structural principles underlying the composition of protective antiviral monoclonal antibody (mAb) cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic mAb cocktail against Ebola virus. We systematically analyzed the antibody repertoire in human survivors and identified a pair of potently neutralizing mAbs that cooperatively bound to the ebolavirus glycoprotein (GP). High-resolution structures revealed that in a two-antibody cocktail, molecular mimicry was a major feature of mAb-GP interactions. Broadly neutralizing mAb rEBOV-520 targeted a conserved epitope on the GP base region. mAb rEBOV-548 bound to a glycan cap epitope, possessed neutralizing and Fc-mediated effector function activities, and potentiated neutralization by rEBOV-520. Remodeling of the glycan cap structures by the cocktail enabled enhanced GP binding and virus neutralization. The cocktail demonstrated resistance to virus escape and protected non-human primates (NHPs) against Ebola virus disease. These data illuminate structural principles of antibody cooperativity with implications for development of antiviral immunotherapeutics.
Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Ebolavirus/immunology , Glycoproteins/immunology , Hemorrhagic Fever, Ebola/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Cell Line , Disease Models, Animal , Drug Therapy, Combination , Epitopes , Female , Glycoproteins/chemistry , Hemorrhagic Fever, Ebola/prevention & control , Humans , Immunoglobulin Fab Fragments/immunology , Macaca mulatta , Male , Mice , Mice, Inbred BALB C , Molecular Mimicry , Protein ConformationABSTRACT
Autoimmune pancreatitis (AIP) is an uncommon variant of chronic pancreatitis characterized by inflammatory changes within the pancreatic tissue triggered by autoimmune mechanisms. It is known to mimic pancreatic cancer due to its similar clinical and radiological presentations. We underline a case of a 55-year-old male who presented with weight loss, jaundice, and pruritus. Radiological imaging suggested a pancreatic mass, raising suspicion of malignancy. However, subsequent evaluation, absence of parenchymal tissue and lymphoplasmacytic cells on endoscopic ultrasound-guided biopsy, and elevated serum immunoglobulin G4 level resulted in the diagnosis of AIP. Our case emphasizes that AIP should be included in the differential diagnosis of obstructive jaundice, especially when clinical and radiological findings are inconclusive for pancreatic cancer.