肥大细胞(MC)是强大的炎性免疫前哨细胞,可驱动许多过敏,炎症,和瘙痒障碍时激活。MC靶向疗法在几种疾病中得到批准,然而,许多患者获益有限,提示需要更广泛抑制MC活性的方法.MCs需要KIT受体及其配体干细胞因子(SCF)进行分化,成熟,和生存。在这里,我们描述了CDX-0159,一种抗KIT单克隆抗体,可有效抑制人类健康志愿者的MC。
使用表达KIT的永生化细胞和原代人肥大细胞在体外测试CDX-0159介导的KIT抑制。CDX-0159的安全性和药代动力学在13周良好实验室规范(GLP)-符合食蟹猴研究中进行评估。单次递增剂量(0.3、1、3和9mg/kg),进行了双盲安慰剂对照1a期人类健康志愿者研究(n=32)以评估安全性,药代动力学,和CDX-0159的药效学。
CDX-0159在体外抑制SCF依赖性KIT活化。CDX-0159中的Fc修饰导致效应子功能的消除和降低的血清清除率。在猕猴中,多个高剂量安全给药,对血液学无显著影响,KIT抑制剂的潜在担忧。在健康人受试者中的单剂量的CDX-0159通常是良好耐受的,并且证明了长时间的抗体暴露。重要的是,CDX-0159导致剂量依赖性,血浆类胰蛋白酶的深度抑制,一种与组织MC负荷相关的MC特异性蛋白酶,提示全身MC抑制或消融。
CDX-0159给药导致全身性肥大细胞消融,可能是治疗肥大细胞驱动的疾病的一种安全且新颖的方法。
Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the
KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers.
CDX-0159-mediated
KIT inhibition was tested in vitro using
KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque
study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer
study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159.
CDX-0159 inhibits SCF-dependent
KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation.
CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.