Autoimmunity, Transplantation and Inflammation, Novartis Institutes of Biomedical Research, Basel, Switzerland.
Translational Medicine, Novartis Institutes of Biomedical Research, Basel, Switzerland.
Am J Transplant. 2018 Dec;18(12):2895-2904. doi: 10.1111/ajt.14872. Epub 2018 May 24.
The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.
CD40-CD154 共刺激途径对于 T 细胞依赖性免疫反应、体液记忆的发展和抗原呈递细胞功能至关重要。这些免疫功能与多种自身免疫性疾病以及同种异体移植物排斥的发病机制有关。我们已经开发出 CFZ533，这是一种完全人源化的、阻断 CD40 的单克隆抗体，经过 N297A 突变修饰，使其无法介导 Fcγ 依赖性效应功能。CFZ533 抑制 CD154 诱导的人白细胞体外激活，但未能诱导人白细胞激活。此外，CFZ533 无法介导人表达 CD40 的 B 细胞耗竭。在体内，CFZ533 阻断了非人类灵长类动物的原发性和回忆性 T 细胞依赖性抗体反应，并消除了生发中心的形成，而外周血 B 细胞未被耗竭。我们还在组织中建立了 CFZ533 的血浆浓度与 CD40 途径相关药效学效应之间的关系。这些数据共同支持了该抗体在某些自身免疫性疾病和实体器官移植中的临床应用的科学原理和剂量方案。
