Targeting toxins to tumors using microproteins

使用微生物蛋白将毒素靶向肿瘤

基本信息

  • 批准号:
    7609247
  • 负责人:
  • 金额:
    $ 53.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-06 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Treatment of metastatic tumors is a major health challenge. Recently, antibody-based therapies have been developed that are more specific and have fewer side effects compared with conventional chemotherapy. However, the potency of most antibody therapeutics is limited by their inadequate ability to kill tumor cells. Consequently, there is an urgent, unmet need to develop therapeutics that combine the specificity of antibodies for tumor tissues with a potent cytotoxic function. The development of tumor-targeted toxins has yielded promising results and led to one approved product, Ontak (Denileukin). Most molecules however are immunogenic and aggregation prone, have limited stability and require complex manufacturing routes. To achieve clinical and commercial success it is critical for candidates to meet following criteria: 1) high potency; 2) low systemic toxicity; 3) low immunogenicity; 4) high protein stability, lack of aggregation; 5) robust manufacturing. This proposal aims to develop tumor-targeted toxins by combining three elements that confer significant advantages over current approaches: microproteins for tumor binding/internalization; RNAse for cell killing; rPEG to optimize PK properties. In the successful Phase I of this project, we developed tumor-specific microproteins with the following properties: 1) efficient production in E. coli; 2) efficient phage display that enables rapid specificity optimization; 3) effective internalization of toxic payloads; 4) excellent serum stability. In a separate phase I SBIR project, we developed rPEGs, hydrophilic protein sequences that mimic the properties of chemical polyethylene glycol (PEG) but can be directly fused to other proteins. rPEGs optimize the pharmacokinetics of a product, reduce product immunogenicity, and greatly reduce protein aggregation. Our Phase II goal is to optimize the specificity of our lead microproteins to achieve a >1000x ration of tumor/normal affinity. Subsequently, we will fuse these optimized microproteins to RNAse as toxic payload and rPEG to optimize PK, PD and protein manufacturing. The resulting fusion proteins will be thoroughly evaluated for in vitro and in vivo performance. In addition, we will develop an effective manufacturing process that can be transferred with minor modifications to a GMP manufacturer. We aim to generate two lead molecules that will be ready to enter preclinical followed by clinical development. In addition we will generate microprotein-rPEG fusions with defined conjugation sites that will be uniquely suitable for the chemical conjugation of toxic payloads. PUBLIC HEALTH RELEVANCE: The development of tumor-targeted toxins have yielded promising results and led to one approved product, Denileukin. However, existing molecules have significant limitations especially immunogenicity and complex manufacturing requirements. This project will use tumor-specific microproteins to address these limitations and develop targeted toxins with the following characteristics: 1) high potency; 2) low systemic toxicity; 3) low immunogenicity to allow repeat dosing; 4) good protein stability; 5) lack of aggregation; 6) robust manufacturing process.
描述(由申请人提供):转移性肿瘤的治疗是一项重大的健康挑战。最近,基于抗体的疗法已经开发出来,与传统化疗相比,其特异性更强,副作用更少。然而,大多数抗体治疗剂的效力受限于其杀死肿瘤细胞的能力不足。因此,迫切需要开发将抗体对肿瘤组织的特异性与有效的细胞毒性功能结合的联合收割机。肿瘤靶向毒素的开发已经产生了有希望的结果,并导致了一种批准的产品Ontak(Denileukin)。然而,大多数分子具有免疫原性和聚集倾向,具有有限的稳定性,并且需要复杂的制造路线。为了实现临床和商业成功,候选物满足以下标准至关重要:1)高效力; 2)低全身毒性; 3)低免疫原性; 4)高蛋白稳定性,无聚集; 5)稳健的制造。该提案旨在通过结合三种元素来开发肿瘤靶向毒素,这三种元素具有优于当前方法的显著优势:用于肿瘤结合/内化的微蛋白;用于细胞杀伤的RNA酶;用于优化PK特性的rPEG。在该项目的第一阶段,我们开发了具有以下特性的肿瘤特异性微蛋白:1)在E.大肠杆菌; 2)能够实现快速特异性优化的高效噬菌体展示; 3)有效内化毒性有效载荷; 4)优异的血清稳定性。在一个单独的I期SBIR项目中,我们开发了rPEG,这是一种亲水性蛋白质序列,模拟了化学聚乙二醇(PEG)的特性,但可以直接与其他蛋白质融合。rPEG优化产品的药代动力学,降低产品免疫原性,并大大减少蛋白质聚集。我们的第二阶段目标是优化我们的先导微蛋白的特异性,以实现> 1000倍的肿瘤/正常亲和力比。随后,我们将这些优化的微蛋白融合到作为毒性有效载荷的RNA酶和rPEG中,以优化PK、PD和蛋白质制造。将全面评价所得融合蛋白的体外和体内性能。此外,我们将开发一种有效的生产工艺,该工艺可以通过微小的修改转移到GMP生产商。我们的目标是产生两种先导分子,这些分子将准备进入临床前,然后进行临床开发。此外,我们将产生微蛋白-rPEG融合与定义的共轭位点,这将是唯一适合于有毒有效载荷的化学共轭。 公共卫生相关性:针对肿瘤的毒素的开发已经取得了可喜的成果,并导致了一种批准的产品,Denileukin。然而,现有的分子具有显著的局限性,特别是免疫原性和复杂的制造要求。该项目将使用肿瘤特异性微蛋白来解决这些限制,并开发具有以下特征的靶向毒素:1)高效力; 2)低全身毒性; 3)低免疫原性,允许重复给药; 4)良好的蛋白质稳定性; 5)缺乏聚集; 6)稳健的制造工艺。

项目成果

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Volker Schellenberger其他文献

Volker Schellenberger的其他文献

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{{ truncateString('Volker Schellenberger', 18)}}的其他基金

XTENylation of enfuvirtide to generate a bio-better product with improved dosing
恩夫韦肽的 XTEN 化可生成具有改进剂量的生物更好的产品
  • 批准号:
    8410855
  • 财政年份:
    2012
  • 资助金额:
    $ 53.19万
  • 项目类别:
Glycine rich sequences with pharmacokinetic enhancing properties of PEG polymers
富含甘氨酸的序列具有 PE​​G 聚合物药代动力学增强特性
  • 批准号:
    7536130
  • 财政年份:
    2007
  • 资助金额:
    $ 53.19万
  • 项目类别:
Glycine rich sequences with pharmacokinetic enhancing properties of PEG polymers
富含甘氨酸的序列具有 PE​​G 聚合物药代动力学增强特性
  • 批准号:
    7678909
  • 财政年份:
    2007
  • 资助金额:
    $ 53.19万
  • 项目类别:
Glycine rich sequences with pharmacokinetic enhancing properties of PEG polymers
富含甘氨酸的序列具有 PE​​G 聚合物药代动力学增强特性
  • 批准号:
    7218864
  • 财政年份:
    2007
  • 资助金额:
    $ 53.19万
  • 项目类别:
Drug binding microprotein domains for targeted delivery of cytotoxic drugs
用于细胞毒性药物靶向递送的药物结合微蛋白结构域
  • 批准号:
    7269631
  • 财政年份:
    2007
  • 资助金额:
    $ 53.19万
  • 项目类别:
Targeting toxins to tumors using microproteins
使用微生物蛋白将毒素靶向肿瘤
  • 批准号:
    7687366
  • 财政年份:
    2007
  • 资助金额:
    $ 53.19万
  • 项目类别:

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