Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
J Am Soc Nephrol. 2022 May;33(5):918-935. doi: 10.1681/ASN.2021030372. Epub 2022 Feb 16.
IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression, with a high risk of kidney failure. Although no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy.
We chose an IgA protease of commensal bacterium , termed AK183, as the template for constructing a recombinant biologic. To extend the in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein toward the cleavage and subsequent clearance of IgA were tested in mouse models.
First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter domain. Therefore, we grafted Fc to the N terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus.
We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy in mouse models.
IgA 肾病是一种常见的原发性肾小球肾炎，由 IgA 复合物在系膜沉积引起。该疾病的临床进展具有多变性，肾衰竭风险较高。尽管尚无特定的治疗方法，但清除 IgA 沉积的酶学策略正被考虑用于治疗快速进展性 IgA 肾病。
我们选择了一种共生菌的 IgA 蛋白酶，命名为 AK183，作为构建重组生物的模板。为了延长在血液中的半衰期，我们将 AK183 与人类 IgG1 的 Fc 段融合。在小鼠模型中测试了这种 Fc-AK183 融合蛋白对 IgA 切割和随后清除的活性。
首先，我们发现了 AK183 的自切割活性，它将 N 端蛋白酶与其 C 端自转运结构域分离。因此，我们将 Fc 嫁接在 AK183 的 N 端，并在小鼠中证明了其长达一周的酶活性。此外，与 Fc-AK183 反应生成的 IgA 蛋白酶解片段被有效地从循环和肾脏过滤中清除。Fc-AK183 介导的切割和随后的 IgA 肾清除的联合作用导致血液 IgA 的持久清除，这在人 IgA 注射模型和人源化转模型中得到了证实。Fc-AK183 还能够清除肾小球中慢性 IgA 和相关的补体 C3 沉积。
我们构建了 IgA 蛋白酶与 Fc 的嵌合融合物，并在小鼠模型中证明了其作为 IgA 肾病有前途的靶向治疗方法的持久疗效。
