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

 描述(由申请者提供)：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治疗干预措施，将羟考酮铅疫苗与通过新型温度敏感凝胶聚合物技术配制的免疫调节剂相结合，以增强疫苗接种后的抗体(Ab)反应。物质使用障碍(SUD)疫苗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疫苗没有达到预期，但在获得高水平抗药物血清抗体的免疫受试者子集中证明了原理。抗体的产生是次级淋巴器官生发中心(GC)T细胞依赖的B细胞分化的结果。GC依赖的抗原特异性B细胞和T细胞的分化受细胞因子(如白介素类)、共刺激分子和免疫检查点控制的特定信号通路的调控。大量的临床前研究已经验证了半抗原和生物偶联化学、佐剂、多肽和蛋白质载体、脂质体-蛋白质纳米颗粒或基于聚合物的纳米颗粒是否可以改善SUD疫苗的效果。相比之下，还没有研究测试可用免疫调节剂的广泛范围，这些调节剂彻底改变了癌症和自身免疫性疾病的免疫治疗。使用模型疫苗60XY-KLH，我们的团队已经确定了疫苗接种后抗体和疫苗效力的免疫学机制，我们目前正在利用这些靶点来开发更有效的SUD疫苗。在一项寻找潜在的铅免疫调节剂的筛选研究中，我们发现6OXY-KLH与IL-4或阻断IL-2信号的单抗(MAb)联合应用，可以增加对羟考酮的疗效。为了将6OXY-KLH与IL-4和/或其他免疫调节剂有效地结合在一个合适的注射配方中，我们与I-Novion合作，I-Novion是一家专门从事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。AIM1将测试60OXY-KLH和选定的免疫调节剂的组合是否能改善接种后小鼠的抗羟考酮抗体、60XY特异性B细胞和疫苗效果。AIM2将测试PBC辅助分娩是否改善了60XY-KLH的疗效，并从AIM1引出。AIM3将测试AIM1和AIM2引线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注射方面的有效性。大鼠的自我给药。完成这些目标将产生对处方阿片滥用的免疫治疗干预，为cGMP生产和IND支持研究做好准备。该项目的完成将为加强疫苗接种后抗体反应的新的基于机制的战略提供数据支持，该战略可应用于其他SUD或具有挑战性的疾病的疫苗，如艾滋病毒、疟疾或癌症。

 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.