Drug-Free Macromolecular Therapeutics

无药大分子治疗

• 批准号: 10062492
• 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/10062492
• 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CD 20抗体（奥法木单抗和奥比妥珠单抗（OBN））显著 改善非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）的治疗。单独或 联合化疗（例如R-CHOP，与环磷酰胺，阿霉素， 长春新碱和泼尼松），它们产生了更好的临床结果。然而，复发经常发生， 患者预后差。2017年，美国估计有72，240例NHL新发病例， 20，110例新CLL病例和4，660例男性和女性死亡。这表明需要 以改进治疗策略。拟议研究的目标是设计、综合和评价 用于治疗B细胞恶性肿瘤的第二代无药物大分子治疗剂（DFMT）。 抗-CD 20抗体分为I型如RTX和II型如OBN;它们具有不同的免疫原性。 与CD 20受体结合的模式。RTX在CD 20四聚体之间结合，导致脂质蓄积 筏，钙内流和半胱天冬酶激活。OBN结合在一个四聚体内，构象相容 与同型粘附区，导致肌动蛋白细胞骨架重塑和溶酶体破坏。我们 设计通过触发两种类型的细胞凋亡激活途径来增强II型OBN的活性。 抗体的该新系统由两种纳米缀合物组成：a）双特异性缀合物，OBN-M0 RF 1（OBN 缀合至一个吗啉代寡核苷酸MORF 1）;和B）交联（效应物）组分HSA- （M0 RF 2）X（用多个拷贝的互补吗啉代接枝的人血清白蛋白（HSA）） 寡核苷酸2）。用一个M0 RF 1修饰0 BN不影响0 BN-M0 RF 1与M0 RF 1的结合。 CD 20和随后与CD 20结合的II型效应发生。进一步暴露于多价效应物HSA- （MORF 2）X导致OBN-MORF 1-CD 20复合物聚集成脂筏，并发生I型效应。 这种新的方法，称为“集群OBN（cOBN）”结合了两种抗体类型的影响，导致非常 高凋亡水平。在双特异性寡核苷酸中，M0 RF 1将通过硫醚键连接至OBN， OBN二硫键的还原。多价交联效应物HSA-（M0 RF 2）x的结构将 优化以确保cOBN系统在NHL的播散模型上的最高效率。最近， OBN与苯丁酸氮芥的组合被FDA批准。我们已经表明，基于HSA的DFMT敏感 NHL细胞对不同化疗剂的敏感性。因此，我们计划评估将cOBN与 化疗药物对细胞凋亡诱导机制和效率的影响。最后，我们证明了 DFMT对耐药淋巴瘤和从诊断为各种亚型的 B细胞恶性肿瘤。我们将确定对我们的新疗法有良好反应的患者子集。在 总而言之，这个提议在科学上是新颖的，并且具有巨大的转化潜力。此外，它还提供了一个新的 适用于淋巴瘤以外其他疾病的大分子疗法设计范例。