Treatment of Colitis using a Novel CXCR3 Biologic Antagonist

描述（由申请人提供）：克罗恩病（CD）是一种慢性、复发性和组织破坏性炎症性肠病（IBD），非常需要新的治疗方法。据估计，美国每年有> 1百万例IBD病例，其中50%涉及CD。我们的主要目标是开发一种生物制剂，可用于更好地治疗和减少这种毁灭性炎症疾病的体征和症状。当前的提议源于我们的发现，即CXCR 3相互作用增强Th 1免疫反应，并且CXCR 3配体（CXCL 9、CXCL 10和CXCL 11）在CD患者中上调。幸运的是，CD的临床特征与某些结肠炎小鼠模型相关，包括在IL-10-/-小鼠中观察到的自发性结肠炎。该模型为研究IBD和开发治疗这种毁灭性疾病的疗法提供了极好的手段。虽然存在结合CXCR 3的小分子拮抗剂，但这些药物的使用受到其相对低的生物利用度和疏水性质的限制，这通常与肝脏和心脏毒性相关。为了解决这个问题并治疗大部分由B CXCR 3相互作用介导的结肠炎，JYANT Technologies开发了一种新的突变CXCR 3配体-免疫球蛋白融合蛋白（mut-CXCL 11-IG），其缺乏免疫原性糖胺聚糖（结缔组织）结合位点，但保留了紧密结合但不激活CXCR 3的能力。 因此，该提议将检验mut-CXCL 11-IG可以抑制CXCR 3相互作用以减轻结肠炎的体征和症状的假设。两个具体目的将用于测试该假设以开发我们的新型蛋白质药物：目的1将确定mut-CXCL 11-IG的药效学/药代动力学（PK/PD）特征。目的2评价mut-CXCL 11-IG治疗和预防自发性结肠炎的疗效及其免疫原性和毒性。目的3将使用（18种不同的）人CCR 1 -10、CXCR 1 -7和CX 3CR 1全细胞PathHunter（r）？表征mut-CXCL 11-IG的任何脱靶趋化因子受体活性。抑制蛋白活性测定和CXCR 3配体介导的人CD 4 + T细胞趋化性测定。

DESCRIPTION (provided by applicant): There is a great need for new therapies for Crohn's disease (CD), which is a chronic, relapsing and tissue destructive inflammatory bowel disease (IBD). Estimates indicate that there are > 1 million annual cases of IBD in the United States, 50% of which involve CD. Our primary objective is to develop a biologic that can be used to better treat and reduce the signs and symptoms of this devastating inflammatory disease. The current proposal stems from our findings that CXCR3 interactions enhance Th1 immune responses, and CXCR3 ligands (CXCL9, CXCL10, and CXCL11) are up regulated in CD patients. Fortunately, the clinical features of CD correlate with certain mouse models of colitis, including the spontaneous colitis observed in IL-10-/- mice. This model provides an excellent means to study IBD and develop therapies to treat this devastating disease. While there are small molecule antagonists that bind CXCR3, the use of these pharmaceuticals is limited by their relatively low bioavailability and hydrophobic nature, which are often associated with liver and cardiac toxicities. To solve this problem and to treat colitis that is mediated in large part b CXCR3 interactions, JYANT Technologies has developed a novel mutant CXCR3 ligand-immunoglobulin fusion protein (mut-CXCL11-Ig) that lacks immunogenic, glycosaminoglycan (connective tissues)-binding sites but retains the ability to tightly bind, but not activate CXCR3. Hence, this proposal will test the hypothesis that mut-CXCL11-Ig can inhibit CXCR3 interactions to reduce the signs and symptoms of colitis. Two Specific Aims will be used to test this hypothesis for the development of our novel protein drug: Aim 1 will ascertain the pharmacodynamics/pharmacokinetics (PK/PD) profile of mut-CXCL11-Ig. Aim 2 will assess the efficacy of mut-CXCL11-Ig to treat and prevent spontaneous colitis as well as its immunogenicity and toxicity. Aim 3 will characterize any off target chemokine receptor activity of mut-CXCL11-Ig using (18 different) human CCR1-10, CXCR1-7, and CX3CR1 whole cell PathHunter(r) ?-Arrestin activity assays and CXCR3 ligand-mediated human CD4+ T cell chemotaxis assays.