Iverson G M, Jones D S, Marquis D, Linnik M D, Victoria E J
La Jolla Pharmaceutical Company, San Diego, CA 92121, USA.
Lupus. 1998;7 Suppl 2:S166-9. doi: 10.1177/096120339800700236.
Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of beta2-glycoprotein I (beta2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-beta2-GPI antibodies was investigated. Anti-beta2-GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-beta2-GPI antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-beta2-GPI antibodies in vivo.
抗磷脂综合征的特征是血栓前状态以及存在β2糖蛋白I（β2-GPI）依赖性抗磷脂抗体。研究了基于B细胞耐受性的方法特异性降低抗β2-GPI抗体的可行性。从一名抗磷脂综合征患者分离出的抗β2-GPI抗体用于筛选噬菌体中表达的肽库，从而鉴定出一种能特异性结合抗β2-GPI抗体的噬菌体。对噬菌体展示的肽进行鉴定并进行化学优化，以生成具有内部硫醚键的合成14肽（LJP 685），该肽保留了原始噬菌体的结合特性。将LJP 685与一个确定的、无免疫原性的有机平台偶联，以生成LJP 685的四价展示形式用作耐受原。四价LJP 685可使先前用与载体钥孔血蓝蛋白偶联的LJP 685免疫和加强免疫的小鼠体内抗体水平呈剂量依赖性降低。这些实验支持了基于耐受性的方法在体内降低抗β2-GPI抗体的技术可行性。
