Enhancing efficacy of vaccines for substance abuse through polymer-assisted delivery of immunomodulators

 描述（由申请人提供）：该战略联盟寻求资金，以开发一种针对处方阿片类药物滥用的免疫干预措施，该干预措施将铅羟考酮疫苗与通过新型热敏胶凝聚合物技术配制的免疫调节剂相结合，以增强疫苗接种后抗体（Ab）反应。药物使用障碍疫苗（SUD）有可能成为一种持久，安全，廉价和有效的干预措施。SUD疫苗刺激患者自身的免疫系统产生抗药物抗体，防止药物分布到大脑和药物诱导的行为。第一代SUD疫苗未达到预期，但在获得高水平抗药血清Ab的免疫受试者亚组中证明了原理证明。Ab的产生源于次级淋巴器官中生发中心（GC）中T细胞依赖性B细胞分化。GC依赖性抗原特异性B和T细胞分化受细胞因子（例如，白细胞介素）、共刺激分子和免疫检查点。大量的临床前研究已经测试了SUD疫苗的效力是否可以通过半抗原和生物缀合化学、佐剂、肽和蛋白质载体、脂质体-蛋白质纳米颗粒或基于聚合物的纳米颗粒来提高。相比之下，没有研究测试了广泛的可用免疫调节剂，这些免疫调节剂彻底改变了癌症和自身免疫性疾病的免疫疗法。使用模型疫苗6 OXY-KLH，我们的小组已经确定了免疫接种后抗体和疫苗效力的免疫机制，我们目前正在利用这些目标开发更有效的SUD疫苗。在一项筛选研究中，我们发现6 OXY-KLH与IL-4或阻断IL-2信号传导的单克隆抗体（mAb）联合给药可增加对羟考酮的疗效。为了将6 OXY-KLH与IL-4和/或其他免疫调节剂有效地结合在合适的注射制剂中，我们与i-novion合作，i-novion是一家专注于聚合物技术的初创公司，拥有新型五嵌段共聚物（PBC）的独家所有权。AIM 1将测试6 OXY-KLH和选定的免疫调节剂的组合是否改善小鼠中的疫苗接种后抗羟考酮Ab、6 OXY特异性B细胞和疫苗效力。AIM 2将测试PBC辅助分娩是否改善6 OXY-KLH和AIM 1导线的疗效。AIM 3将测试来自AIM 1和AIM 2的导联在阻断羟考酮诱导的小鼠纹状体多巴胺释放和条件性位置偏爱以及羟考酮静脉内自我给药大鼠中的有效性。这些目标的完成将为处方阿片类药物滥用产生免疫干预，为cGMP生产和IND使能研究做好准备。该项目的完成将提供数据支持一种新的基于机制的策略，用于增强疫苗接种后的抗体反应，该策略可应用于其他SUD或挑战性疾病（如艾滋病毒、疟疾或癌症）的疫苗。

 DESCRIPTION (provided by applicant):This Strategic Alliance seeks funding to develop an immunotherapeutic intervention for prescription opioid abuse that combines a lead oxycodone vaccine with immunomodulators formulated through a novel thermosensitive gelling polymer technology to enhance the post-vaccination antibody (Ab) response. Vaccines for substance use disorders (SUD) have the potential to be a long-lasting, safe, cheap, and effective intervention. Vaccines for SUD stimulate the patient's own immune system to produce anti-drug Ab that prevent drug distribution to the brain and drug-induced behavior. First-generation SUD vaccines did not meet expectations, yet demonstrated proof-of-principle in the subset of immunized subjects that achieved high levels of anti-drug serum Ab. Generation of Ab results from T cell-dependent B cell differentiation in germinal centers (GC) in secondary lymphoid organs. GC-dependent antigen-specific B and T cell differentiation is regulated by specific signaling pathways controlled by cytokines (e.g., interleukins), co- stimulatory molecules, and immune checkpoints. A wealth of pre-clinical studies have tested whether the efficacy of SUD vaccines can be improved by hapten and bioconjugation chemistry, adjuvant, peptides and protein carriers, liposome-protein nanoparticle, or polymer-based nanoparticles. In contrast, no studies have tested the broad range of available immunomodulators, which have revolutionized immunotherapy for cancer and autoimmune diseases. Using the model vaccine 6OXY-KLH, our group has identified immunological mechanisms underlying post-vaccination Ab and vaccine efficacy, and we are currently exploiting these targets for developing more effective SUD vaccines. In a screening study to identify potential lead immunomodulators, we found that co-administration of 6OXY-KLH with IL-4, or a monoclonal Ab (mAb) that blocks IL-2 signaling, increased efficacy against oxycodone. To effectively combine the 6OXY-KLH with IL-4 and/or other immunomodulators in a suitable injectable formulation, we have partnered with i-novion, a start-up company specialized in polymer technology, which has exclusive ownership of novel pentablock co-polymers (PBC). AIM1 will test whether combination of 6OXY-KLH and selected immunomodulators improves post-vaccination anti-oxycodone Ab, 6OXY-specific B cells, and vaccine efficacy in mice. AIM2 will test whether PBC-assisted delivery improves efficacy of 6OXY-KLH and leads from AIM1. AIM3 will test the efficacy of leads from AIM1 and AIM2, in blocking oxycodone-induced striatal dopamine release and conditioned place preference in mice, and oxycodone i.v. self-administration in rats. Completion of these aims will generate an immunotherapeutic intervention for prescription opioid abuse, ready for cGMP production and IND enabling studies. Completion of this project will provide data supporting a novel mechanism-based strategy for enhancing post-vaccination Ab responses, which could be applied to vaccines for other SUD or challenging diseases such as HIV, malaria, or cancer.