Targeting lymphoma with modular anti-idiotype peptibodies

用模块化抗独特型肽体靶向淋巴瘤

• 批准号: 8716890
• 负责人: James Anthony Torchia
• 金额: $ 2.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-14 至 2015-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716890
• 关键词: Adoption; Affinity; Animal Model; Antibodies; Apoptosis; B-Cell Lymphomas; B-Lymphocytes; Biological Models; Cancer Patient; Cell Line; Cells; Chemicals; Clonal Deletion; Combination Drug Therapy; Complement; Complementarity Determining Regions; Custom; Cysteine; Cytolysis; Disease Management; Drug Kinetics; Engineering; Engraftment; Fc domain; Generations; Growth; Half-Life; Hematologic Neoplasms; Human; Immune; Immunoglobulin G; Immunoglobulin Idiotypes; Immunoglobulins; In Vitro; Lead; Ligands; Ligation; Link; Luciferases; Lymphoma; MS4A1 gene; Malignant - descriptor; Mediating; Methods; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Non-Hodgkin' s Lymphoma; Non-Malignant; Patients; Peptides; Phagocytosis; Pharmaceutical Preparations; Population; Progressive Disease; Property; Receptor Signaling; Recombinants; Relapse; Relative (related person); Research; S phase; SCID Mice; Shapes; Signal Transduction; Solid; Surface; Surface Immunoglobulins; Techniques; Testing; Therapeutic; Toxic effect; Translations; Treatment Efficacy; Work; Xenograft Model; Xenograft procedure; anergy; antibody-dependent cell cytotoxicity; cancer cell; cancer therapy; cost; design; high throughput screening; immunoglobulin receptor; improved; in vivo; mouse model; novel; outcome forecast; public health relevance; standard of care; synthetic construct; synthetic peptide; therapeutic target; tumor

Current therapies for non-hodgkin lymphoma (NHL) are initially effective for most patients but result in diminished efficacy and cumulative toxicity with repeated use and the majority of patients relapse and succumb to progressive disease (1). A more targeted therapy that utilizes a novel mechanism of action would be a welcome addition to the arsenal of therapies available for management of this disease. The majority of NHL tumors arise from a clonal population of B-cells. The complementarity determining region (CDR) of the surface immunoglobulin receptor, also known as idiotype, is nearly identical on all malignant cells in B-cell lymphomas and is distinct from the idiotype present on non-malignant B-cells. Thus, idiotype is a true tumor-specific surface marker and an attractive candidate for targeted cancer therapy. Antibodies against idiotype have been shown to induce complete regression of lymphoma in patients (3). But since the idiotype on each patient's cancer is unique, this therapeutic approach requires the generation of a custom monoclonal antibody for each patient - a requirement that raises technical and practical barriers that prohibit the widespread translation of this approach. We are developing a method of targeting idiotype that may be more practical to scale. Short peptides with targeted affinity for idiotype can be identified by high throughput screens, produced rapidly and inexpensively by automated solid-phase synthesis, and can directly induce apoptosis of lymphoma cells in-vitro (4, 5). Although these peptides appear to be poor drugs in animal models, affixing them to the amino terminus of an IgG Fc domain might improve their potency by extending their pharmacokinetic half-life and by augmenting their anti-tumor effect through activation of innate immune effector mechanisms. Since the patient-specific portion would be a short synthetic peptide and the biologic Fc domain would be produced in bulk for all patients, this approach may be more practical than producing a unique biologic monoclonal antibody for each patient. We hypothesize that this semi-synthetic construct, that we term a "modular peptibody", will be sufficient for lymphoma tumor clearance of a human lymphoma xenograft in a murine model system.

目前的非霍奇金淋巴瘤（NHL）治疗最初对大多数患者有效，但结果是， 重复使用会降低疗效和累积毒性，大多数患者会复发， 死于进行性疾病（1）。利用新的作用机制的更有针对性的治疗将 是一个受欢迎的除了阿森纳的治疗可用于管理这种疾病。 大多数NHL肿瘤来自B细胞的克隆群体。的互补性 表面免疫球蛋白受体的决定区（CDR），也称为独特型， 在B细胞淋巴瘤的所有恶性细胞上，与非恶性B细胞上存在的独特型不同。 因此，独特型是一种真正的肿瘤特异性表面标记物，是一种有吸引力的靶向癌症治疗的候选者。 抗独特型抗体已显示可诱导患者淋巴瘤完全消退（3）。但 由于每个患者癌症的独特型是独特的，这种治疗方法需要产生一种 为每个患者定制单克隆抗体--这一要求提出了技术和实际障碍， 禁止这种做法的广泛翻译。 我们正在开发一种针对独特型的方法，这种方法可能更实用。短肽 具有针对独特型的靶向亲和力，可以通过高通量筛选鉴定，快速产生， 通过自动化固相合成廉价地合成，并且可以在体外直接诱导淋巴瘤细胞凋亡 〔四、五〕。虽然这些肽在动物模型中似乎是差的药物，但将它们连接到氨基末端， IgG Fc结构域的增加可能通过延长其药代动力学半衰期和通过增加其活性来改善其效力。 通过激活先天免疫效应机制增强其抗肿瘤作用。以来 患者特异性部分将是短的合成肽，并且生物Fc结构域将在体内产生。 对于所有患者来说，这种方法可能比生产一种独特的生物单克隆抗体更实用。 为每位患者提供抗体。 我们假设，这种半合成的构建体，我们称之为“模块化肽体”， 足以在鼠模型系统中清除人淋巴瘤异种移植物的淋巴瘤肿瘤。