Drug-Free Macromolecular Therapeutics

无药大分子治疗

• 批准号: 9885447
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9885447
• 关键词: Actins; Adhesions; Antibodies; Apoptosis; Apoptotic; B lymphoid malignancy; Binding; CD20 Antigens; Calcium; Caspase; Cell surface; Cells; Cessation of life; Chlorambucil; Chronic Lymphocytic Leukemia; Clinical; Complex; Cyclophosphamide; Cytoskeleton; Diagnosis; Disease; Disease Resistance; Doxorubicin; Ensure; Evaluation; Exposure to; FDA approved; Female; Follicular Lymphoma; Generations; Genes; Genetic; Goals; Half-Life; Heavy-Chain Immunoglobulins; Human; In Vitro; Induction of Apoptosis; Length; Lymphoma; Lymphoma cell; Lysosomes; MS4A1 gene; Mantle Cell Lymphoma; Mediating; Membrane Microdomains; Modeling; Modification; Molecular Conformation; Nanoconjugate; Non-Hodgkin' s Lymphoma; Oligonucleotides; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Prednisone; Recurrent disease; Relapse; Resistance; Sampling; Serum Albumin; Somatic Mutation; Structure; System; Testing; Therapeutic; Time; Treatment Efficacy; Vertebral column; Vincristine; anti-CD20; base; chemotherapeutic agent; chemotherapy; crosslink; design; disulfide bond; drug efficacy; flexibility; improved; in vivo; in vivo evaluation; indexing; large cell Diffuse non-Hodgkin' s lymphoma; macromolecule; male; mutational status; neonatal Fc receptor; novel; novel drug class; novel strategies; novel therapeutics; patient subsets; prognostic; receptor; response; rituximab; thioether; tositumomab; treatment strategy; tumor

Rituximab (RTX) and other anti-CD20 antibodies (ofatumumab and obinutuzumab (OBN)) dramatically improved treatment of Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Alone or in combination with chemotherapy (e.g. R-CHOP, a combination with cyclophosphamide, doxorubicin, vincristine, and prednisone) they produced better clinical outcomes. However, relapses frequently occur with poor patient outcomes. In 2017 in the USA, there were an estimated 72,240 new cases of NHL and 20,140 deaths, 20,110 new cased of CLL and 4,660 deaths in both males and females. This demonstrates the need for improved treatment strategies. The goal of the proposed studies is to design, synthesize, and evaluate the second generation of drug-free macromolecular therapeutics (DFMT) for the treatment of B-cell malignancies. Anti-CD20 antibodies are divided into Type I such as RTX and Type II such as OBN; they have different patterns of binding to CD20 receptor. RTX binds between CD20 tetramers resulting in accumulation in lipid rafts, calcium influx and caspase activation. OBN binds within one tetramer with the conformation compatible with homotypic adhesion regions, leading to actin cytoskeleton remodeling and lysosome disruption. Our design enhances the activity of Type II OBN by triggering the apoptosis activation pathways of both types of antibodies. This new system is composed of two nanoconjugates: a) bispecific engager, OBN-MORF1 (OBN conjugated to one morpholino oligonucleotide MORF1); and b) a crosslinking (effector) component HSA- (MORF2)X (human serum albumin (HSA) grafted with multiple copies of complementary morpholino oligonucleotide 2). Modification of OBN with one MORF1 does not impact the binding of OBN-MORF1 to CD20 and following binding to CD20 Type II effects occur. Further exposure to multivalent effector HSA- (MORF2)X results in clustering the OBN-MORF1-CD20 complexes into lipid rafts and Type I effects occur. This new approach, called “clustered OBN (cOBN)” combines effects of both antibody types resulting in very high apoptotic levels. In the bispecific engager, MORF1 will be attached to OBN via thioether bond following reduction of OBN's disulfide bonds. The structure of the multivalent crosslinking effector HSA-(MORF2)x will be optimized to ensure the highest efficiency of the cOBN system on disseminated models of NHL. Recently, combination of OBN with chlorambucil was FDA approved. We have shown that HSA-based DFMT sensitizes NHL cells to different chemotherapeutic agents. Thus we plan to evaluate the impact of combining cOBN with chemotherapeutics on the mechanism and efficiency of apoptosis induction. Finally, we demonstrated efficacy of DFMT on resistant lymphomas and cells isolated from patients diagnosed with various subtypes of B cell malignancies. We shall identify subsets of patients that respond favorably to our new therapeutics. In summary, this proposal is scientifically novel and has great translational potential. Also, it provides a new paradigm for the design of macromolecular therapeutics applicable to other diseases beyond lymphomas.

利妥昔单抗(RTX)和其他抗CD20抗体(Ofatumumab和obinutuzumab(OBN) 改进非霍奇金淋巴瘤(NHL)和慢性淋巴细胞白血病(CLL)的治疗。独自一人或在 联合化疗(例如R-CHOP，与环磷酰胺、阿霉素、 长春新碱和强的松)，它们产生了更好的临床结果。然而，复发经常发生在 病人的预后很差。2017年，美国估计有72,240例新的NHL病例和20,140例新病例 死亡，20110例慢性淋巴细胞性白血病新病例，4660例男性和女性死亡。这证明了有必要 以改善治疗策略。建议研究的目标是设计、综合和评估 治疗B细胞恶性肿瘤的第二代无药物大分子疗法(DFMT)。 抗CD20抗体分为I型如RTX和II型如OBN；它们有不同的 与CD20受体结合的模式。RTX与CD20四聚体结合导致脂质蓄积 木筏、钙内流和半胱氨酸氨基转移酶激活。OBN结合在一个构象相容的四聚体中 具有同型粘附区，导致肌动蛋白细胞骨架重塑和溶酶体破坏。我们的 设计通过触发两种类型的OBN的凋亡激活途径来增强II型OBN的活性 抗体。这个新的体系由两个纳米偶联物组成：a)双特异性结合物OBN-MORF1(OBN 结合到一个吗啉寡核苷酸MORF1)；和b)交联(效应物)组分HSA- (MORF2)X(人血清白蛋白)与多拷贝互补吗啉 寡核苷酸2)。用一个MORF1修饰OBN不影响OBN-MORF1与 CD20及以下与CD20的第二类结合效应发生。进一步暴露于多价效应器HSA- (MORF2)X导致OBN-MORF1-CD20复合体聚集成脂筏，并发生I类效应。 这种新的方法，称为“簇状OBN(COBN)”，结合了两种抗体类型的效果，导致非常 高水平的细胞凋亡。在双功能分子中，MORF1将通过以下硫醚键连接到OBN上 OBN的二硫键的还原。多价交联效应器HSA-(MORF2)x的结构将 进行优化，以确保cOBN系统在传播的非霍奇金淋巴瘤模型上具有最高效率。最近， OBN与氯氨丁苯的联合应用获得了FDA的批准。我们已经证明，基于人血清白蛋白的DFMT具有敏感性 NHL细胞对不同化疗药物的敏感性。因此，我们计划评估将cOBN与 化疗药物诱导细胞凋亡的机制和效率。最后，我们演示了 DFMT对耐药淋巴瘤及不同亚型白血病患者分离细胞的疗效 B细胞恶性肿瘤。我们将确定对我们的新疗法反应良好的患者亚群。在……里面 综上所述，这项建议在科学上是新颖的，具有很大的翻译潜力。此外，它还提供了一种新的 适用于淋巴瘤以外其他疾病的大分子疗法设计范例。