A New Anti-CD27 Monoclonal Antibody Adjuvant for Pancreatic Cancer Vaccines

描述（由申请人提供）：蛋白质疫苗的免疫原性较弱，但我们已经开始通过将单克隆抗体中的胰腺癌蛋白靶向摄取树突状细胞（DC）上的受体来克服这一障碍。 我们强调在交叉呈递中有活性的DC，例如DEC-205+ DC。 从包括我们自己在内的许多实验室的研究来看，CD 70--CD 27的肿瘤坏死因子家族配体--现在被认为是启动T细胞免疫、T细胞在肿瘤中积累和T细胞长期存活的主要贡献者。DC上CD 70的表达受到严格控制，但CD 27总是在幼稚T细胞上表达。 我们假设激动性抗CD 27抗体将是一种上级佐剂，通过确保CD 70信号的传递来提高胰腺癌疫苗的功效。这可以通过新的可用工具来实现。 我们建议探索一种新的针对huCD 27的全人单克隆抗体，作为DC靶向胰腺癌蛋白疫苗的更有效佐剂。我们还将使用人CD 27转基因小鼠模型，这两种新工具都是由Celldex Therapeutics开发的。为了获得原理证明，我们将首先使用抗CD 27与异种胰腺抗原、人间皮素、HuMSLN组合，其在抗DEC-205 mAb内靶向。我们将评估T细胞免疫的数量、质量和持续时间。抗-CD 27还将与多聚IC和激动性抗-CD 40的组合进行比较，该组合是DC上CD 70表达的最强大的已知诱导剂。 我们接下来将使用稳定转导以表达huMSLN的Panc 02胰腺可移植肿瘤评估抗CD 27在预防和治疗方案中的功效。在更具挑战性的环境中，我们将测试人抗huCD 27是否可以有效地指导小鼠克服对自身/小鼠间皮素的自身耐受性。我们主要想确定允许T细胞免疫进入肿瘤微环境并发挥作用的疫苗条件。总之，我们的研究计划将开辟一个新的领域，以改善疫苗接种的胰腺癌抗原，间皮素，表达的大多数胰腺癌。 这一提议的影响不仅是为人类开辟了抗CD 27方法，并为胰腺癌带来了一种易于耐受的DC靶向蛋白疫苗方法，而且还扩大了胰腺癌免疫评估的范围，在CD 4+和CD 8 + T细胞特性的水平上，特别是持久性和进入可移植肿瘤的能力。这些临床前研究的所有组成部分均设计为在本提案的2年内快速进入临床试验，前提是假设证明抗CD 27是一种综合和持久T细胞免疫的上级佐剂。 公共卫生相关性：该提案将为胰腺癌疫苗开辟一个新的维度，使用新的全人源抗人CD 27单克隆抗体作为佐剂或免疫增强剂。 该提案将为关键的CD 27途径带来宝贵的新资源，该途径可以提高对癌症的抵抗力，但除此之外，该提案还使用了树突状细胞靶向蛋白疫苗，该疫苗可以扩展到包括几种抗原，重要的是，已经在健康志愿者中显示出免疫原性。 的所有组件 这些临床前研究被设计为在该提议的两年中，如果假设的抗-CD 27被证明是用于整合和持久的T细胞免疫的上级佐剂，则快速进入临床测试。

DESCRIPTION (provided by applicant): Protein vaccines have suffered from weak immunogenicity but we have begun to overcome this obstacle by targeting pancreatic cancer proteins within monoclonal antibodies to uptake receptors on dendritic cells (DC). We emphasize DCs active in cross presentation such as DEC-205+ DCs. From research in many labs including our own, CD70 -- the tumor necrosis factor family ligand for CD27 -- is now appreciated to be a major contributor for initiating T cell immunity, accumulation of T cells in te tumor, and long term T cell survival. The expression of CD70 on DCs is tightly controlled, but CD27 is always expressed on na¿ve T cells. We hypothesize that agonistic anti-CD27 antibody will be a superior adjuvant to improve the efficacy of pancreatic cancer vaccines, by ensuring delivery of the CD70 signal. This can be approached with new available tools. We propose to explore a new fully human Mab against huCD27 as a more effective adjuvant for a DC-targeted pancreatic cancer protein vaccine. We will also use a human CD27 transgenic mouse model, with both of these new tools being developed by Celldex Therapeutics. To obtain proof-of-principle, we will first use anti-CD27 in combination with a xenogenic pancreatic antigen, human mesothelin, HuMSLN, targeted within anti-DEC-205 mAb. We will assess the quantity, quality and duration of T cell immunity. Anti-CD27 will also be compared to the combination of poly IC and agonistic anti-CD40, a combination that is the most powerful known inducer of CD70 expression on DCs. We will next assess the efficacy of anti-CD27 in both prophylactic and therapeutic protocols using the Panc02 pancreatic transplantable tumor that is stably transduced to express huMSLN. In a more challenging setting, we will test if human anti-huCD27 can efficiently instruct mice to overcome self-tolerance to self/mouse mesothelin. We mainly want to identify vaccine conditions that allow T cell immunity to enter and function in the tumor microenvironment. In summary, our research plan will open up a new field to improve vaccination to a pancreatic cancer antigen, mesothelin, expressed by most pancreatic cancers. The impact of this proposal is not only to open up the anti-CD27 approach for humans, and to bring a readily tolerated DC-targeted protein vaccine approach to pancreatic cancer, but also to expand the scope of pancreatic cancer immune evaluation, at the level of CD4+ and CD8+ T cell properties especially durability and entry into transplantable tumors. All components of these preclinical studies are designed to be brought into clinical testing quickly, within the 2 years of this proposal, if anti-CD27 as hypothesized proves to be a superior adjuvant for integrated and durable T cell immunity. PUBLIC HEALTH RELEVANCE: This proposal will open a new dimension to pancreatic cancer vaccines using a new fully human anti-human CD27 monoclonal antibody as an adjuvant or immune booster. The proposal will bring valuable new resources to the pivotal CD27 pathway that can improve resistance to cancer, but in addition the proposal uses a dendritic cell-targeting protein vaccine that can be expanded to include several antigens and importantly, is already showing immunogenicity in healthy volunteers. All components of these preclinical studies are designed to be brought into clinical testing quickly, witin the two years of this proposal, if anti-CD27 as hypothesized proves to be a superior adjuvant for integrated and durable T cell immunity.