Abstract
Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. However, some patients repeatedly receiving rHuEPO develop anti-rHuEPO neutralizing antibodies leading to the development of pure red cell aplasia (PRCA). The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB1*09 gene, which is reported to be entrenched in the Thai population. In this study, we used computational design to screen for immunogenic hotspots recognized by HLA-DRB1*09, and predicted seventeen mutants having anywhere between one through four mutations that reduce affinity for the allele, without disrupting the structural integrity and bioactivity. Five out of seventeen mutants were less immunogenic in vitro while retaining similar or slightly reduced bioactivity than rHuEPO. These engineered proteins could be the potential candidates to treat patients who are rHuEpo-dependent and express the HLA-DRB1*09 allele.
Highlights
Recombinant human erythropoietin is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia
Several reports have shown that the number of reported cases with pure red cell aplasia (PRCA) due to the development of neutralizing antibodies against endogenous EPO and recombinant erythropoiesis-stimulating agents (ESAs) has increased worldwide[7,8,9,10,11,12,13]
While PRCA is a type of anemia associated with several causes including virus infection, immunological mediation, pregnancy, pre-stage malignancy, toxic exposure, and drug effects, the distinct features of PRCA associated with Recombinant human erythropoietin (rHuEPO) includes severe rHuEPO resistance, blood transfusion dependence, high serum ferritin, bone marrow showing the absence of red cell precursor and presence of anti-rHuEPO antibody[15,16]
Summary
Recombinant human erythropoietin (rHuEPO) is a biopharmaceutical drug given to patients who have a low hemoglobin related to chronic kidney disease, cancer or anemia. The immunogenic antibody response activated by rHuEPO is believed to be triggered by T-cells recognizing EPO epitopes bound to MHC molecules displayed on the cell surface of APCs. Previous studies have reported an association between the development of anti-rHuEpo-associated PRCA and the HLA-DRB1*09 gene, which is reported to be entrenched in the Thai population. Several reports have shown that the number of reported cases with PRCA due to the development of neutralizing antibodies against endogenous EPO and recombinant erythropoiesis-stimulating agents (ESAs) has increased worldwide[7,8,9,10,11,12,13] Most of these reported cases were in patients receiving rHuEPO for the treatment of CKD-related anemia.
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