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

 描述（由申请人提供）：Navidea Biopharmaceuticals正在寻求SBIR快速通道资助，用于临床前动物研究和监管1/2期临床研究。 99 mTc-tilmanocept鉴别类风湿性关节炎（RA）引起的骨关节炎的能力。类风湿关节炎是一种慢性、进行性、全身性、自身免疫性疾病，以骨关节炎为特征。如果治疗不成功，RA可导致残疾，毁容和过早死亡。最近，抗风湿药物（DMARDs）已显着改善许多RA患者的预后。仍然存在三个问题：1 ]当RA症状首次出现时，DMARD最有效，这对于当前的RA诊断是有问题的; 2 ]监测DMARD治疗的有效性是具有挑战性的; 3 ]相当一部分RA患者对当前的DMARD反应不佳或根本没有反应。因此，对于更准确的RA诊断，特别是对于早期RA，以及对于更有效的RA治疗，存在显著未满足的医学/临床需求。通过该应用程序，Navidea正在努力解决这些临床关键需求。99 mTc-Tilmanocept是一种完全合成的分子，专门设计用于以高亲和力结合巨噬细胞甘露糖受体（CD 206）。99 mTc-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，这是99 mTc-tilmanocept已获得FDA批准的适应症。99 mTc-Tilmanocept与肿瘤相关淋巴结中巨噬细胞上展示的CD 206结合。在RA中，大量表达CD 206的巨噬细胞浸润到发炎关节的滑膜间隙中。用RA小鼠模型进行的动物研究表明，99 mTc-替马诺塞可以静脉注射，然后在RA炎症关节中特异性蓄积。在人滑膜抽吸物的离体测试中，Cy 3-替马诺塞强烈区分RA与骨关节炎和健康对照组织。在本申请中，提出了额外的动物研究，以确保静脉注射99 mTc-替马诺塞的安全性。然后在临床研究中，99 mTc-tilmanocept将静脉注射到四种类型的研究中 参加者：12名活动性RA参与者，30名最近发生多关节痛（PAT）的参与者，12名50岁以上的健康无关节炎个体，以及12名非RA引起的关节疼痛患者。PAT可能有许多原因，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。早期诊断对RA患者的治疗效果最好，可在最有效的时候进行DMARD治疗。将通过单光子发射计算机断层扫描（SPECT）对注射99 mTc Tc-tilmanocept的受试者进行成像。本研究将调查99 mTc-tilmanocept识别RA炎症关节和在PAT患者中识别早期RA患者的能力。后续研究将调查替马诺塞是否也可以将治疗药物靶向递送到RA炎症关节，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.