ABSTRACT

Tumor necrosis factor (TNF) and interleukin (IL)-17A are pleiotropic cytokines implicated in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). JNJ-61178104 is a novel human anti-TNF and anti-IL-17A monovalent, bispecific antibody that binds to both human TNF and human IL-17A with high affinities and blocks the binding of TNF and IL-17A to their receptors in vitro. JNJ-61178104 also potently neutralizes TNF and IL-17A-mediated downstream effects in multiple cell-based assays. In vivo, treatment with JNJ-61178104 resulted in dose-dependent inhibition of cellular influx in a human IL-17A/TNF-induced murine lung neutrophilia model and the inhibitory effects of JNJ-61178104 were more potent than the treatment with bivalent parental anti-TNF or anti-IL-17A antibodies. JNJ-61178104 was shown to engage its targets, TNF and IL-17A, in systemic circulation measured as drug/target complex formation in normal cynomolgus monkeys (cyno). Surprisingly, quantitative target engagement assessment suggested lower apparent in vivo target-binding affinities for JNJ-61178104 compared to its bivalent parental antibodies, despite their similar in vitro target-binding affinities. The target engagement profiles of JNJ-61178104 in humans were in general agreement with the predicted profiles based on cyno data, suggesting similar differences in the apparent in vivo target-binding affinities. These findings show that in vivo target engagement of monovalent bispecific antibody does not necessarily recapitulate that of the molar-equivalent dose of its bivalent parental antibody. Our results also offer valuable insights into the understanding of the pharmacokinetics/pharmacodynamics and target engagement of other bispecific biologics against dimeric and/or trimeric soluble targets in vivo.

摘要

肿瘤坏死因子（TNF）和白介素（IL）-17A是涉及多种自身免疫性疾病（包括类风湿关节炎（RA）和银屑病关节炎（PsA））的发病机制的多效细胞因子。JNJ-61178104是新型人抗TNF和抗IL-17A单价双特异性抗体，可与人TNF和人IL-17A高亲和力结合，并在体外阻断TNF和IL-17A与它们的受体的结合。JNJ-61178104还可以在多种基于细胞的测定中有效中和TNF和IL-17A介导的下游效应。体内，在人IL-17A / TNF诱导的鼠肺中性粒细胞增多症模型中，JNJ-61178104的处理导致剂量依赖性的细胞涌入抑制作用，JNJ-61178104的抑制作用比二价亲本抗TNF或抗IL-17A抗体。已显示JNJ-61178104在系统循环中与靶标TNF和IL-17A结合，以正常食蟹猴（cyno）猴中的药物/靶标复合物形成来衡量。出人意料的是，定量靶标参与评估表明，尽管JNJ-61178104在体外具有相似的亲和力，但其在体内的靶标结合亲和力却较低目标结合亲和力。JNJ-61178104在人体内的靶标参与图谱与基于食蟹猴数据的预测图谱基本吻合，表明在体内靶标结合亲和力方面存在相似的差异。这些发现表明，单价双特异性抗体的体内靶标结合并不一定能概括其二价亲本抗体的摩尔当量剂量。我们的结果还提供了对体内药代动力学/药效学和其他双特异性生物制剂针对二聚体和/或三聚体可溶性靶标的靶标结合的理解的宝贵见解。