A Rapid, High Performance, Cost-Efficient Clinical Scale Separator for CD3+ cells

一种快速、高性能、经济高效的 CD3 细胞临床规模分离器

基本信息

  • 批准号:
    9047881
  • 负责人:
  • 金额:
    $ 27.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-02-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The notion of adoptive cellular immunity was first conceived and reported by A.V. Mitchison1 more than 60 years ago. Since then extraordinary human effort and ingenuity has resulted in fundamental understandings of molecular biology, the immune system, genetics, gene therapy and the dreaded disease cancer. That has enabled the creation of incredible tools - inconceivable a generation ago - which has put medical science on the threshold of cancer cures. One part of that 'tool box' is the isolation of subsets o immune cells from patients/donors and the purification of genetically modified cells. Currently, CD3+ cells are the prime targets of such separations. Cost effective/efficient separations are vitally important given the expense such treatments entail. The goal of this proposal is to test the feasibility of a clinical scale immuno-magnetic cell separation system that has the potential to be faster (3-fold), cheaper (2-fold) and better (yield & purity) for the isolation of CD3 + cell than the system of Miltenyi Biotec and other improvised systems in use at many centers. This proposal is based on extraordinary benefits our magnetic nanoparticles confer to cell separations. These ferrofluids are crystalline quasi-spherical 120 nm cores of magnetite crystals coated with modified protein to which common capture agents (streptavidin, antibodies) or Mabs (direct conjugates) are coupled. They are stable, have been in commercial use more than 10 years and are the key component of the FDA-approved CellSearch(r) circulating tumor cell enrichment scheme. Benefits: (a) rapid binding kinetics as they diffuse (b) extraordinary surface area; thus, low mass input for targeting (c) most magnetic superparamagnetic materials in existence (greater than 95% magnetite - most magnetic superparamagnetic material) (d) easy to GMP manufacture and filter sterilize (e) separable from open vessels (test tubes, flow through chambers/closed containers vs. Miltenyi's that require ultra-high gradient magnetic forces, ball bearing packed, expensive and inefficient columns. With in-house designed magnetic devices, ferrofluids can collect cells in monolayers or multilayers that are easily retrievable. Unlike larg Dynal Dynabeads, ferrofluids do not damage cells, clutter up cell surfaces nor affect cell viability. This work benefits from 3 years of extensive R&D in improving our ferrofluids' magnetics and surface chemistries resulting in use of less material, significantly lower non-specific binding and improved purity as well as more latitude in collection chamber design because of their magnetics. From fundamental discoveries on cell separation, that use very little Mab, it is feasible to target 30% of a 1010 cell starting product with 30 ug of Mab (vs 1000 ug for competing systems) and with only 4 mg of 5th generation ferrofluid. And the entire separation can be done in less than 30 minutes. Our skill set/ experience: PI founded/managed Immunicon Corp., conceived of CellSearch(r), designed seminal experiments showing that tumor cells circulate early on in cancers, recruited the development team for commercial and FDA approved system and started the corporate partnership with Johnson & Johnson. All of that began with a Phase I SBIR. 1 . A.V. Mitchison, J Exp Med. 1955 Aug 1; 102(2): 157-177. [The PI was fortunate to have had the benefit of close contact and interactions with Av Mitchison (University College, London) while the PI was a Visiting Scientist at NIMR, Mill Hill working in the laboratory of the late Bridgette Askonas. We had many discussions on how to use the immune system to attack malignancies.]
 描述(由申请人提供):过继性细胞免疫的概念最早由A. V. Mitchison 1在60多年前提出并报道。从那时起,人类非凡的努力和创造力导致了对分子生物学,免疫系统,遗传学,基因治疗和可怕的疾病癌症的基本理解。这使得创造出令人难以置信的工具成为可能--这在一代人之前是不可想象的--这使医学科学走上了治愈癌症的门槛。该“工具箱”的一部分是从患者/供体中分离免疫细胞亚群和纯化遗传修饰细胞。目前,CD 3+细胞是这种分离的主要目标。考虑到这种处理所需的费用,成本有效/高效的分离是至关重要的。本提案的目的是测试临床规模免疫磁性细胞分离系统的可行性,该系统在分离CD 3+细胞方面比Miltenyi Biotec系统和许多中心使用的其他简易系统更快(3倍),更便宜(2倍)和更好(产量和纯度)。这项提议是基于我们的磁性纳米颗粒赋予细胞分离的非凡益处。这些铁磁流体是包覆有改性蛋白质的磁铁矿晶体的晶体准球形120 nm核,常见的捕获剂(链霉亲和素、抗体)或Mab(直接缀合物)与所述改性蛋白质偶联。它们是稳定的,已经在商业上使用了10多年,是FDA批准的CellSearch(r)循环肿瘤细胞富集方案的关键组成部分。优点:(a)扩散时的快速结合动力学(B)超常的表面积;因此,用于靶向(c)存在的大多数磁性超顺磁性材料的低质量输入(大于95%的磁铁矿-大多数磁性超顺磁性材料)(d)易于GMP制造和过滤灭菌(e)可与开口容器(试管,与Miltenyi的相比,其需要超高梯度磁力、滚珠轴承填充、昂贵且低效的柱。通过内部设计的磁性装置,铁磁流体可以收集单层或多层的细胞,这些细胞很容易回收。与大型Dynal Dynabeads不同,铁磁流体不会损伤细胞,不会扰乱细胞表面,也不会影响细胞活力。这项工作得益于3年的广泛研发,以改善我们的铁磁流体的磁性和表面化学,从而使用更少的材料,显着降低非特异性结合和提高纯度,以及更多的自由度,在收集室设计,因为他们的磁性。从使用非常少的Mab的细胞分离的基本发现来看,用30 μ g Mab靶向1010个细胞起始产物的30%是可行的(相对于1000 μ g Mab)。 竞争系统),并且仅使用4毫克的第五代铁磁流体。整个分离过程可以在30分钟内完成。我们的技能组合/经验:PI创立/管理Immunicon Corp.,该公司构思了CellSearch(r),设计了开创性的实验,显示肿瘤细胞在癌症早期循环,为商业和FDA批准的系统招募了开发团队,并开始与约翰逊和约翰逊合作。所有这一切都始于第一阶段SBIR。1 . A. V. Mitchison,J Exp Med. 1955年8月1日; 102(2):157-177。[The PI有幸与Av Mitchison(大学学院,伦敦)密切接触和互动,而PI是NIMR的访问科学家,在实验室米尔希尔工作 已故的布里奇特·阿斯科纳斯我们就如何利用免疫系统攻击恶性肿瘤进行了多次讨论。

项目成果

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