Hakimi J, Chizzonite R, Luke D R, Familletti P C, Bailon P, Kondas J A, Pilson R S, Lin P, Weber D V, Spence C
Department of Immunopharmacology, Hoffman-La Roche, Inc., Nutley, NJ 07110.
J Immunol. 1991 Aug 15;147(4):1352-9.
The anti-Tac mAb has been shown to bind to the p55 chain of the IL-2R, block IL-2 binding and inhibit T cell proliferation. A humanized form of anti-Tac (HAT) has been constructed that retains the binding properties of murine anti-Tac (MAT). These two mAb were evaluated in cynomolgus monkeys to compare relative immunogenicity and pharmacokinetic properties. Monkeys treated with HAT daily for 14 days exhibited anti-HAT antibody titers which were 5- to 10-fold lower than their MAT-treated counterparts and these antibodies developed later than in the MAT-treated monkeys. Two of four monkeys receiving a single injection of MAT developed anti-MAT antibodies, whereas none of four monkeys developed antibodies after a single treatment with HAT. In monkeys injected with either HAT or MAT daily for 14 days, the anti-antibody titers induced were inversely related to the amount of anti-Tac administered. Antibodies that developed against MAT were both anti-isotypic and anti-idiotypic, whereas those developed against HAT appeared to be predominantly anti-idiotypic. The pharmacokinetic properties, that is the half-life and area under the curve values, of HAT were also significantly different from those of MAT. The area under the curve values for HAT in naive monkeys were approximately twofold more than those for MAT, and the mean serum half-life of HAT was 214 h, approximately four- to fivefold more than MAT. These pharmacokinetic values were reduced in monkeys previously sensitized with HAT or MAT suggesting that the presence of anti-antibodies altered these parameters.
抗 Tac 单克隆抗体已被证明可与白细胞介素 -2 受体的 p55 链结合，阻断白细胞介素 -2 的结合并抑制 T 细胞增殖。已构建出一种人源化形式的抗 Tac（HAT），它保留了鼠抗 Tac（MAT）的结合特性。对食蟹猴进行了这两种单克隆抗体的评估，以比较它们的相对免疫原性和药代动力学特性。每天用 HAT 治疗 14 天的猴子所产生的抗 HAT 抗体滴度比用 MAT 治疗的同类猴子低 5 至 10 倍，且这些抗体出现的时间比用 MAT 治疗的猴子更晚。接受单次 MAT 注射的四只猴子中有两只产生了抗 MAT 抗体，而接受单次 HAT 治疗的四只猴子中没有一只产生抗体。在每天注射 HAT 或 MAT 持续 14 天的猴子中，诱导产生的抗抗体滴度与所给予的抗 Tac 量呈负相关。针对 MAT 产生的抗体既有抗同种型的也有抗独特型的，而针对 HAT 产生的抗体似乎主要是抗独特型的。HAT 的药代动力学特性，即半衰期和曲线下面积值，也与 MAT 有显著差异。未接触过抗体的猴子中 HAT 的曲线下面积值大约是 MAT 的两倍，HAT 的平均血清半衰期为 214 小时，大约是 MAT 的四至五倍。在用 HAT 或 MAT 预先致敏的猴子中，这些药代动力学值降低，这表明抗抗体的存在改变了这些参数。
