Methods for improving the properties of antibody-drug conjugates

改善抗体-药物缀合物性质的方法

• 批准号: 8714998
• 负责人: David Y Jackson
• 金额: $ 21.57万
• 依托单位: IGENICA, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714998
• 关键词: Address; Antibodies; Antigen Targeting; Antigens; Antineoplastic Agents; Biological Factors; Businesses; Cause of Death; Cells; Clinical; Collaborations; Consultations; Cysteine; Cytotoxic agent; Data; Development; Disulfides; Drug usage; Excision; FDA approved; Goals; Half-Life; Heterogeneity; Hospitals; In Vitro; Industry; Inhibitory Concentration 50; Insurance; Insurance Carriers; Letters; Light; MCF7 cell; Malignant Neoplasms; Marketing; Measures; Methods; Mitotic; Modeling; Monoclonal Antibodies; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Positioning Attribute; Principal Investigator; Process; Property; Proteins; Provider; Quality of life; Research; Safety; Technology; Therapeutic; Time; Toxic effect; Trastuzumab; Treatment Cost; Tubulin; Tumor Antigens; Universities; analog; cost; covalent bond; cytotoxic; design; drug discovery; effective therapy; experience; improved; in vivo; inhibitor/antagonist; innovation; malignant breast neoplasm; neoplastic cell; novel; novel strategies; oncology; pre-clinical; professor; public health relevance; quantum; research and development; screening; success; therapeutic target; tumor

DESCRIPTION (provided by applicant): Antibody drug conjugates (ADCs), a rapidly growing class of targeted therapeutics, represent a promising new approach toward improving both the selectivity and the cytotoxic activity of cancer drugs. Although several ADCs have demonstrated recent clinical success, the utility of most ADCs currently in development is limited by cumbersome synthetic processes, insufficient anti-tumor activity, and unpredictable toxicity. We believe that these drawbacks can be addressed by improvements in both linker technology and the cytotoxic drugs used to construct the ADCs. Our broad long-term goal is to develop novel ADCs with improved potency, homogeneity and stability over existing targeted therapeutics. Igenica has developed two proprietary technology platforms that provide a complementary function-oriented screening strategy to systematically identify novel tumor associated antigen targets and antigen-specific monoclonal antibodies for constructing ADCs with improved pharmacological properties. First, we have designed a novel bifunctional linker strategy that enables synthesis of ADCs with improved homogeneity and stability over conventional ADCs. These improvements will reduce the amount of cytotoxic drug payload that is released systemically and result in safer ADCs with longer half- lives in vivo. Additionally, we will utiliz tubulysins, a potent new class of anti-mitotic natural products, which are more potent than current ADC drug payloads. Our preliminary data indicates that tubulysins are up to 1000 times more potent than the currently utilized ADC payload, MMAF. Two specific aims are proposed. Aim 1) To demonstrate that novel bi-functional linkers can be used to construct homogeneous ADCs with improved stability. Aim 2) to demonstrate that tubulysins can be utilized to construct ADCs with improved potency. The Phase I milestones are designed to demonstrate the feasibility of using Igenica's innovative linkers and drug payloads by comparing ADCs that contain the clinically validated tumor specific antibody, Trastuzumab. In Phase II of this project we will combine the novel linkers and payloads described in Phase 1 and apply them to a novel tumor specific antibody. We will evaluate the resulting novel ADCs in relevant tumor models. If successful, these technologies will be applied to other antibodies in development for different indications and will ultimately have a significant impact on the fields of drug discovery and cancer therapeutics.

描述（由申请人提供）：抗体药物共轭物（ADC）是一种迅速增长的靶向治疗剂，代表了一种有希望的新方法，用于提高癌症药物的选择性和细胞毒性活性。尽管几个ADC已证明了最近的临床成功，但目前正在开发的大多数ADC的实用性受到繁琐的合成过程，抗肿瘤活性不足和无法预测的毒性的限制。我们认为，这些缺点可以通过接头技术和用于构建ADC的细胞毒性药物的改进来解决。我们广泛的长期目标是开发新的ADC，对现有的靶向治疗方法提高了效力，同质性和稳定性。伊吉尼卡（Igenica）开发了两个专有的技术平台，它们提供了互补的面向功能的筛查策略，以系统地识别新型肿瘤相关的抗原靶标和抗原特异性的单克隆抗体，用于构建具有改进药理特性的ADC。首先，我们设计了一种新型的双功能连接器策略，该策略能够合成与常规ADC相对于常规ADC的均匀性和稳定性提高的ADC。这些改进将减少有系统释放的细胞毒性药物有效载荷的量，并导致更安全的ADC在体内寿命更长。此外，我们将使用一种有效的新型抗溶性天然产品来利用微管蛋白，比目前的ADC药物有效载荷更有效。我们的初步数据表明，微管蛋白素的效力是当前使用的ADC有效载荷MMAF的1000倍。提出了两个具体目标。目的1）证明可以使用新型的双功能接头来构建具有提高稳定性的同质ADC。目标2）证明可以利用微管蛋白来构建具有提高效力的ADC。 I阶段里程碑旨在通过比较包含临床验证的肿瘤特异性抗体Trastuzumab的ADC来证明使用Igenica的创新连接器和药物有效载荷的可行性。在该项目的第二阶段中，我们将结合第1阶段中描述的新型接头和有效载荷，并将其应用于新型的肿瘤特异性抗体。我们将评估相关肿瘤模型中所得的新型ADC。如果成功，这些技术将用于开发的其他抗体，以实现不同的适应症，并最终将对药物发现和癌症治疗剂的领域产生重大影响。