Fernandez Christian A, Smith Colton, Yang Wenjian, Daté Mihir, Bashford Donald, Larsen Eric, Bowman W Paul, Liu Chengcheng, Ramsey Laura B, Chang Tamara, Turner Victoria, Loh Mignon L, Raetz Elizabeth A, Winick Naomi J, Hunger Stephen P, Carroll William L, Onengut-Gumuscu Suna, Chen Wei-Min, Concannon Patrick, Rich Stephen S, Scheet Paul, Jeha Sima, Pui Ching-Hon, Evans William E, Devidas Meenakshi, Relling Mary V
Department of Pharmaceutical Sciences, and.
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN;
Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 Jun 26.
Asparaginase is a therapeutic enzyme used to treat leukemia and lymphoma, with immune responses resulting in suboptimal drug exposure and a greater risk of relapse. To elucidate whether there is a genetic component to the mechanism of asparaginase-induced immune responses, we imputed human leukocyte antigen (HLA) alleles in patients of European ancestry enrolled on leukemia trials at St. Jude Children's Research Hospital (n = 541) and the Children's Oncology Group (n = 1329). We identified a higher incidence of hypersensitivity and anti-asparaginase antibodies in patients with HLA-DRB1*07:01 alleles (P = 7.5 × 10(-5), odds ratio [OR] = 1.64; P = 1.4 × 10(-5), OR = 2.92, respectively). Structural analysis revealed that high-risk amino acids were located within the binding pocket of the HLA protein, possibly affecting the interaction between asparaginase epitopes and the HLA-DRB1 protein. Using a sequence-based consensus approach, we predicted the binding affinity of HLA-DRB1 alleles for asparaginase epitopes, and patients whose HLA genetics predicted high-affinity binding had more allergy (P = 3.3 × 10(-4), OR = 1.38). Our results suggest a mechanism of allergy whereby HLA-DRB1 alleles that confer high-affinity binding to asparaginase epitopes lead to a higher frequency of reactions. These trials were registered at www.clinicaltrials.gov as NCT00137111, NCT00549848, NCT00005603, and NCT00075725.
天冬酰胺酶是一种用于治疗白血病和淋巴瘤的治疗性酶，免疫反应会导致药物暴露不理想以及复发风险增加。为了阐明天冬酰胺酶诱导的免疫反应机制中是否存在遗传成分，我们在圣裘德儿童研究医院（n = 541）和儿童肿瘤学组（n = 1329）参与白血病试验的欧洲血统患者中推算人类白细胞抗原（HLA）等位基因。我们发现携带HLA - DRB1*07:01等位基因的患者中过敏反应和抗天冬酰胺酶抗体的发生率更高（P = 7.5 × 10⁻⁵，比值比[OR] = 1.64；P = 1.4 × 10⁻⁵，OR = 2.92）。结构分析表明，高危氨基酸位于HLA蛋白的结合口袋内，可能影响天冬酰胺酶表位与HLA - DRB1蛋白之间的相互作用。使用基于序列的一致性方法，我们预测了HLA - DRB1等位基因与天冬酰胺酶表位的结合亲和力，并且其HLA遗传学预测为高亲和力结合的患者有更多过敏反应（P = 3.3 × 10⁻⁴，OR = 1.38）。我们的结果提示了一种过敏机制，即赋予与天冬酰胺酶表位高亲和力结合的HLA - DRB1等位基因会导致更高的反应频率。这些试验在www.clinicaltrials.gov上注册，注册号为NCT00137111、NCT00549848、NCT00005603和NCT00075725。
