Drug-Free Macromolecular Therapeutics

无药大分子治疗

• 批准号: 10529277
• 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/10529277
• 关键词: Actins; Adhesions; Albumins; Antibodies; Apoptosis; Apoptotic; B lymphoid malignancy; Binding; CD20 Antigens; Calcium; Caspase; Cell Separation; Cell surface; Cells; Cessation of life; Chlorambucil; Chronic Lymphocytic Leukemia; Clinical; Combined Modality Therapy; Complex; Cyclophosphamide; Cytoskeleton; Diagnosis; Diffuse Large-Cell Lymphoma; Disease; Disease Resistance; Doxorubicin; Ensure; Evaluation; Exposure to; FDA approved; Female; Follicular Lymphoma; Generations; Genes; 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; chemotherapeutic agent; chemotherapy; crosslink; design; disulfide bond; drug efficacy; flexibility; genetic predictors; 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; translational potential; 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））急剧 改善了非霍奇金淋巴瘤（NHL）和慢性淋巴细胞性白血病（CLL）的治疗。单独或在 与化学疗法结合（例如，R-Chop，与环磷酰胺，阿霉素的组合， vincristine和泼尼松）它们产生了更好的临床结果。但是，复发经常发生 病人的结果差。 2017年在美国，估计有72,240例NHL和20,140例 死亡，男性和女性的20,110例新病例和4,660例死亡。这表明需要 改善治疗策略。拟议研究的目的是设计，合成和评估 用于治疗B细胞Malignancys的第二代无药物大分子治疗（DFMT）。 抗CD20抗体分为I型抗体，例如RTX和II型，例如OBN；他们有不同 与CD20受体结合的模式。 RTX在CD20四聚体之间结合，导致脂质积累 筏，钙影响和胱天蛋白酶激活。 OBN与构象兼容的一个四聚体内结合 随着同种型广告区域，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凋亡激活途径来增强II型OBN的活性 抗体。这个新系统由两个纳米缀合物组成：a）双特异性参与者，obn-morf1（obn 与一个morf1寡核苷酸MORF1共轭）； b）交联（效应子）组件HSA- （MORF2）X（人血清白蛋白（HSA），用多个互补的horpholino嫁接 寡核苷酸2）。用一个MORF1修改OBN不会影响OBN-MORF1与 CD20并在结合CD20 II型效应之后。进一步暴露于多价效应子HSA- （MORF2）X导致将OBN-MORF1-CD20复合物聚集到脂质筏中，并发生I型效应。 这种新方法称为“聚集的OBN（COBN）”，结合了两种抗体类型的影响，导致非常 高凋亡水平。在双特异性求职者中，MORF1将通过thioether Bond附在OBN上 减少了OBN的二硫键。多价交联效应子HSA-（MORF2）X的结构将 进行优化，以确保CoBN系统在NHL的传播模型上的最高效率。最近， FDA批准了OBN与Chlorambucil的组合。我们已经表明基于HSA的DFMT灵敏度 NHL细胞与不同的化学治疗剂。我们计划评估将Cobn与 化学治疗药关于凋亡诱导的机制和效率。最后，我们证明了 DFMT对从诊断患有各种亚型的患者分离的耐药性淋巴瘤和细胞的功效 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子集。在 总而言之，该提议在科学上是新颖的，具有巨大的翻译潜力。此外，它提供了一个新的 用于设计大分子疗法的范例，以使其他疾病以外的淋巴瘤范围。