Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 606012, USA.
Department of Surgery, Hollings Cancer Centre, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Clin Immunol. 2014 Jul;153(1):187-98. doi: 10.1016/j.clim.2014.04.014. Epub 2014 May 2.
To prepare a novel Bispecific Antibody (BsAb) as a potential targeted therapy for T1D, we produced a "functionally inert" monoclonal antibody (mAb) against Glucose transporter-2 (GLUT-2) expressed on β-cells to serve as an anchoring antibody. The therapeutic arm is an agonistic mAb against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), a negative regulator of T-cell activation expressed on activated CD4+ T-cells. A BsAb was prepared by chemically coupling an anti-GLUT2 mAb to an agonistic anti-CTLA-4 mAb. This BsAb was able to bind to GLUT2 and CTLA-4 in vitro, and to pancreatic islets, both in vitro and in vivo. We tested the safety and efficacy of this BsAb by treating Non-Obese Diabetes (NOD) mice and found that it could delay the onset of diabetes with no apparent undesirable side effects. Thus, engagement of CTLA-4 on activated T cells from target tissue can be an effective way to treat type-1 diabetes.
为了制备一种新型双特异性抗体（BsAb）作为 T1D 的潜在靶向治疗方法，我们制备了一种针对β细胞上表达的葡萄糖转运蛋白-2（GLUT-2）的“功能惰性”单克隆抗体（mAb）作为锚定抗体。治疗臂是一种针对细胞毒性 T 淋巴细胞抗原 4（CTLA-4）的激动型 mAb，CTLA-4 是一种在激活的 CD4+T 细胞上表达的 T 细胞激活的负调节剂。通过化学偶联将抗 GLUT2 mAb 与激动型抗 CTLA-4 mAb 制备 BsAb。该 BsAb 能够在体外结合 GLUT2 和 CTLA-4，并且能够在体外和体内结合胰岛。我们通过治疗非肥胖型糖尿病（NOD）小鼠来测试该 BsAb 的安全性和疗效，发现它可以延迟糖尿病的发病，且没有明显的不良反应。因此，从靶组织中激活的 T 细胞上结合 CTLA-4 可能是治疗 1 型糖尿病的有效方法。
