Generation of a Therapeutic Antibody Directed Against CCR4 for Patients with

皮肤T细胞淋巴瘤是一组由以下原因引起的异质性淋巴增生性疾病 克隆性来源的皮肤侵袭性T细胞。真菌病和Sezary综合征是最常见的类型 CTCL的数量。目前对晚期疾病患者的治疗方法是姑息和持久的长期治疗。 缓解的情况很少见。使用现有疗法的这些患者的5年存活率很低，这清楚地表明 开发新的靶向疗法来治疗这种致命疾病的重要性。这样做的长期目标是 一项提议是生产一种治疗性的人类单抗(Mab)，它将能够 免疫耗尽恶性CTCL细胞，同时最大限度地减少对已经受损的 免疫系统。基于我们在第一个资助期完成和发布的工作，我们的 选择的靶标是趋化因子受体CCR4，它在CD4+、CLA+上高水平统一表达 CTCL细胞存在于疾病的各个阶段。CCR4已被证明在以下方面具有关键作用 T细胞首先通过与其在介导T细胞的内皮细胞上的配体CCL17相互作用而记忆到皮肤 细胞外渗，然后与仅在局部皮肤微环境中表达的CCL22结合。超过了 在过去的十年里，基于单抗的免疫疗法现在已经成为越来越多的 人类癌症。现在可以使用新的抗体工程技术从头开始分离人的单抗 已经提供了越来越多的处于临床试验所有阶段或已经 获得了FDA的批准。在这五项建议中，我们将使用我们开创性的人类抗体工程工具来 分离出一组高亲和力的人抗CCR4单抗，并将进行广泛的体外和体内研究 目的：评价CTCL免疫治疗的可行性。体外研究将被用来描绘 它们在SCID小鼠CTCL模型和非人灵长类动物体内研究中的作用机制 将验证它们导致CD4+CCR4+细胞免疫耗竭的能力。的长期目标是 这些研究旨在确定一种人源性抗CCR4单抗，该单抗因其最佳结合能力而被选中 体内免疫耗竭的CD4+CCR4+恶性细胞。作为这项提议的一部分，我们将提出我们的时间表 以及将导致IND申请进行L/11期临床试验以评估抗CCR4Mab的计划 晚期CTCL的免疫治疗。

Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders caused by clonally derived, skin-invasive T cells. Mycosis fungoides and Sezary syndrome are the most common types of CTCLs. Current therapies for patients with advanced disease are palliative and durable long-term remissions are rare. The poor 5-year survival of these patients using existing therapies clearly emphasizes the importance of developing new targeted therapies to treat this fatal disease. The long-term goal of this proposal is to produce a therapeutic human monoclonal antibody (Mab) that will be capable of immunodepleting malignant CTCL cells while minimizing collateral damage to an already compromised immune system. Based upon work that we have performed and published in the first funding period, our choice of target is the chemokine receptor CCR4 which is uniformly expressed at high levels on CD4+, CLA+ CTCL cells at all stages of disease. CCR4 has been demonstrated to have a critical role in the migration of memory T cells to the skin first through interactions with its ligand CCL17 on endothelial cells that mediate T cell extravasation and then with CCL22 that is expressed only in the local skin microenvironment. Over the past decade, MAb based immunotherapies have now become standard of care in a growing number of human cancers. Human MAbs can now be isolated de novo using new antibody engineering technologies that have provided a growing number of human Mabs that are in all stages of clinical trials or have already received FDA approval. In this five proposal, we will use our pioneering human antibody engineering tools to isolate a panel of high-affinity human anti-CCR4 Mabs and will conduct extensive in vitro and in vivo studies to evaluate their candidacy for the immunotherapy of CTCL. In vitro studies will be performed to delineate their mechanisms of action while in vivo studies in SCID mouse models of CTCL and in non-human primates will provide validation of their ability to cause immunodepletion of CD4+CCR4+ cells. The long-term goal of these studies is to identify one human anti-CCR4 Mab that has been selected for its ability to optimally immunodeplete CD4+CCR4+ malignant cells in vivo. As part of this proposal, we will present our timetable and plans that will result in an IND filing to conduct a phase l/ll clinical trial to evaluate anti-CCR4 Mab immunotherapy for the treatment of advanced CTCL.