Treatment of Colitis using a Novel CXCR3 Biologic Antagonist

描述(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100万例IBD病例，其中50%与CD有关。我们的主要目标是开发一种生物制剂，可以用来更好地治疗和减少这种破坏性炎症性疾病的症状和体征。目前的建议源于我们的发现，CXCR3相互作用增强Th1免疫反应，CXCR3配体(CXCL9、CXCL10和CXCL11)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。这个模型为研究IBD和开发治疗这种毁灭性疾病的方法提供了一个很好的手段。虽然有结合CXCR3的小分子拮抗剂，但这些药物的使用受到相对较低的生物利用度和疏水性的限制，这往往与肝脏和心脏毒性有关。为了解决这一问题并治疗在很大程度上由CXCR3相互作用介导的结肠炎，JYANT Technologies开发了一种新型突变体CXCR3配体-免疫球蛋白融合蛋白(MUT-CXCL11-Ig)，它缺乏免疫原性、糖胺聚糖(结缔组织)结合部位，但保留紧密结合但不激活CXCR3的能力。 因此，这项建议将检验MUT-CXCL11-Ig可以抑制CXCR3相互作用以减少结肠炎症状和体征的假设。我们将使用两个特定的目标来验证这一假说，以开发我们的新型蛋白质药物：目标1将确定MUT-CXCL11-Ig的药效学/药代动力学(PK/PD)曲线。目的2评价MUT-CXCL11-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用18种不同的人CCR1-10、CXCR1-7和CX3CR1全细胞路径蛋白活性测定和CXCR3配体介导的人CD4+T细胞趋化试验鉴定MUT-CXCL11-Ig的脱靶趋化因子受体活性。

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.