Kovalchin Joseph, King Bracken, Masci Allyson, Hopkins Elizabeth, Fry Jeremy, Hou Jay, Li Christian, Tenneson Kelly, Weber Steve, Wolfe Gary, Collins Kathy, Furfine Eric S
Eleven Biotherapeutics (J.K., B.K., A.M., J.H., K.C., and E.S.F.), Cambridge, MA; Gary Wolfe Toxicology (G.W.), Herndale, VA Sapidyne (E.H.), Boise, ID; ProImmune (J.F.), Oxford, United Kingdom; Charles River (C.L., K.T.), Senneville, QC, Canada; and PharmOptima (S.W.), Portage, MI.
Eye Contact Lens. 2018 May;44(3):170-181. doi: 10.1097/ICL.0000000000000414.
Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1β and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits.
In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase).
EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies.
Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 μL 3 times daily in each eye).
局部应用白细胞介素（IL）-1受体（R）1阻滞剂在减轻干眼症的体征和症状方面具有治疗活性。在此，我们描述了EBI-005的体外和体内非临床研究性新药（IND）支持性研究，EBI-005是一种新型的IL-1β与IL-1受体拮抗剂（IL-1Ra或阿那白滞素）的蛋白嵌合体，能有效结合IL-1R1并阻断信号传导。这些研究评估了其在小鼠和兔子体内的受体亲和力、药物生物利用度、免疫原性反应、安全性和耐受性。
在小鼠和兔子中进行体外、计算机模拟以及符合良好实验室规范（GLP）和非GLP的体内研究，以评估EBI-005的局部眼部和全身免疫原性及毒理学。动物分别通过皮下每日给药一次或局部眼部每日给药四次，持续长达6周（有2周恢复期），接受EBI-005治疗。
EBI-005对IL-1R1的亲和力比阿那白滞素高500倍。预测性免疫原性测试表明EBI-005的免疫原性并不更强。局部眼部给药后，EBI-005的全身生物利用度较低（小鼠为1.4%，兔子为0.2%）。局部眼部给药后15分钟内，EBI-005可渗透到眼前部组织。然而，4小时后其含量较低或无法检测到，且重复局部眼部给药后不会形成药物贮库。基于IND支持性毒理学和安全药理学研究，EBI-005安全且耐受性良好，尽管全身给药后出现抗药抗体反应，但仍能维持药物暴露。
在小鼠和兔子中，以50mg/mL的眼部剂量给予EBI-005，小鼠每只眼总量为0.15mg，兔子每只眼总量为1.5mg，每日给药4次，未产生不良反应，且在目标组织中显示出良好的生物利用度，全身暴露量低。此外，在大多数情况下，对该药物的免疫原性反应未引起不良反应或降低药物活性。这些结果支持给予20mg/mL溶液的最高预期人体临床研究剂量（每只眼每日3次，每次40μL）进行药物给药。
