99mTc-Tilmanocept for Targeting Rheumatoid Arthritis (RA)-Driving Macrophages

 描述(由申请人提供)：Navidea BiopPharmticals正在为临床前动物研究和调节性1/2期临床研究寻求SBIR快速通道拨款支持 99mTc-tilmanocept对类风湿关节炎(RA)骨性关节炎症的识别能力。类风湿关节炎是一种以骨骼关节炎症为特征的慢性、进行性、全身性自身免疫性疾病。如果治疗不成功，类风湿关节炎可能导致残疾、毁容和过早死亡。最近，抗风湿药物(DMARDS)显著改善了许多RA患者的预后。三个问题仍然存在：1)DMARDS在RA症状首次出现时最有效，这对当前的RA诊断是有问题的；2)监测DMARD治疗的有效性具有挑战性；3)相当一部分RA患者对当前的DMARDS反应很差或根本没有反应。因此，对于更准确的类风湿性关节炎诊断，特别是早期类风湿性关节炎，以及更有效的类风湿性关节炎治疗，存在着重大的未得到满足的医疗/临床需求。通过这一应用，Navidea正在发起旨在满足这些临床关键需求的努力。99mTC-Tilmanocept是一种完全人工合成的分子，专为与巨噬细胞甘露糖受体(CD206)高亲和力结合而设计。99mTc-tilmanocept最初的预期用途是在癌症手术期间对前哨淋巴结进行成像，这一适应症已获得FDA的批准。99mTC-Tilmanocept与肿瘤相关淋巴组织中巨噬细胞表达的CD206结合。在RA中，大量表达CD206的巨噬细胞渗入炎症关节的滑膜间隙。对类风湿性关节炎小鼠模型的动物研究表明，99mTC-替马诺普可以静脉注射，然后在类风湿性关节炎的关节中特异性蓄积。在一项人体滑膜抽吸物的体外试验中，Cy3-tilmanocept强烈区分了RA与骨关节炎和健康对照组织。在这项申请中，建议进行更多的动物研究，以确保静脉注射99mTc-替马诺普的安全性。然后，在临床研究中，99mTC-替马诺普将被静脉注射到四种类型的研究中 研究对象：12例活动期RA患者，30例新近发展为多关节痛(PAT)的患者，12例50岁以上无关节炎的健康受试者，12例非RA引起的关节疼痛患者。PAT可能有很多原因，RA只是其中之一。大约2/3的PAT患者预计在1年内进展为坦率的RA。正是这些患者中的RA患者，早期诊断将使他们受益，使他们能够在最有效的时候接受DMARD治疗。注射99mTC-替马诺普的参与者将通过单光子发射计算机断层扫描(SPECT)进行成像。本研究将探讨99mTc-tilmanocept对RA炎症关节的识别能力，以及在PAT患者中识别早期RA患者的能力。后续研究将调查替马诺普是否也可以针对RA炎症关节提供治疗药物，从而实现更好的治疗。

 DESCRIPTION (provided by applicant): Navidea Biopharmaceuticals is seeking SBIR Fast Track grant support for preclinical animal studies and a regulatory phase 1/2 clinical study of the ability of 99mTc-tilmanocept to identify skeletal joint inflammation due to rheumatoid arthritis (RA). RA is a chronic, progressive, systemic, autoimmune disease characterized by skeletal joint inflammation. If not treated successfully, RA can lead to disability, disfigurement and premature death. Recently, antirheumatic drugs (DMARDs) have dramatically improved outcomes for many RA patients. Three problems persist: 1 ] DMARDs are most effective when RA symptoms first appear, which is problematic for current RA diagnostics; 2 ] monitoring the effectiveness of DMARD therapy is challenging; and 3 ] a significant portion of RA patients respond poorly or not at all to current DMARDs. Therefore, there are significant unmet medical/clinical needs for a more accurate RA diagnostic, especially for early stage RA, and for more effective RA therapies. With this application, Navidea is initiating efforts intended to address these clinically pivotal needs. 99mTc- Tilmanocept is a wholly synthetic molecule designed specifically to bind with high affinity to macrophage mannose receptors (CD206). The original intended use for 99mTc-tilmanocept was for imaging sentinel lymph nodes during cancer surgeries, an indication for which 99mTc-tilmanocept has received FDA approval. 99mTc-Tilmanocept binds to CD206 displayed on macrophages residing in tumor associated lymph nodes. In RA, large numbers of CD206 expressing macrophages infiltrate into the synovial spaces of inflamed joints. An animal study with a mouse model of RA showed that 99mTc-tilmanocept can be injected intravenously and thereafter accumulates specifically in RA-inflamed joints. In an ex vivo test of human synovial aspirates, Cy3-tilmanocept strongly differentiated RA from osteoarthritis and healthy control tissue. In this application, additional animal studies are proposed to ensure the safety of injecting 99mTc-tilmanocept intravenously. Then in a clinical study, 99mTc-tilmanocept will be injected intravenously into four types of study participants: 12 participants with active RA, 30 participants with recent development of polyarthralgia (PAT), 12 healthy, arthritis free individuals over the age of 50, and 12 patients with painful joints not caused by RA. PAT may have many causes, of which RA is only one. About 2/3 of PAT patients are expected to progress to frank RA in =1 yr. It is the RA patients among these patients that would benefit m o s t from early diagnosis so that they can receive DMARD therapy when it is most effective. Participants injected with 99mTc Tc-tilmanocept will be imaged by single-photon emission computed tomography (SPECT). This study will investigate the ability of 99mTc-tilmanocept to identify RA inflamed joints and to identify early RA patients among those with PAT. Follow on studies will investigate if tilmanocept can also target delivery of therapeutics to RA inflamed joints, thus enabling better therapies.