Antibody-CpG conjugates for the treatment of B cell lymphoma

抗体-CpG 缀合物用于治疗 B 细胞淋巴瘤

基本信息

批准号：
8616724
负责人：
John M Timmerman
金额：
$ 30.07万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616724
关键词：
Adopted Agonist Animals Antibodies Apoptotic B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Base Sequence Binding CD19 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Culture Techniques Cell Line Cells Chemicals Chemistry Clinical Clinical Research Combined Modality Therapy Complement Complement-Dependent Cytotoxicity Development Employee Strikes Enhancing Antibodies Genetic Engineering Growth Human Immune Immunity Immunocompetent Immunoconjugates Immunodeficient Mouse Immunologic Adjuvants Immunotherapy Inbred BALB C Mice Injection of therapeutic agent Interferons Investigation Laboratories Link Lymphoma MS4A1 gene Maleimides Malignant Neoplasms Mediating Modeling Monoclonal Antibodies Monoclonal Antibody CD20 Mus Natural Killer Cells Non-Hodgkin&apos s Lymphoma Patients Property Reagent Relapse Reporting Resistance Roche brand of rituximab Secondary to Site Specimen Structure Surface Antigens T cell response T-Lymphocyte TLR9 gene Techniques Testing Therapeutic Time Transgenic Mice Translations Tumor Antigens Tumor Immunity Vertebral column Xenograft procedure antibody-dependent cell cytotoxicity antigen binding clinically relevant efficacy testing functional improvement improved in vivo in vivo Model macrophage mouse model novel pre-clinical prevent public health relevance rituximab subcutaneous tositumomab tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Anti-CD20 monoclonal antibodies (mAbs) such as rituximab have become a cornerstone in the therapy of B cell non-Hodgkin lymphomas (NHL), but are only partially effective, as most patients eventually relapse and remain "incurable". While current genetic engineering and efforts are yielding mAbs with enhanced antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and pro-apoptotic functions, these improvements are largely incremental, and do not result in mAbs capable of altering the tumor microenvironment and adjacent host immune cells to favor immune- mediated tumor destruction. We hypothesize that the efficacy of anti-lymphoma mAbs can be improved by linking these precise tumor-targeting vehicles to immunomodulatory substances for release within the tumor microenvironment. Our laboratory has now collected a unique set of cell line models and anti-CD20 reagents including murine lymphomas expressing human CD20, human CD20 transgenic mice, and anti-murine CD20 mAbs that for the first time allow detailed modeling of anti-CD20 therapy in immunocompetent hosts. Toll-like receptor 9 (TLR9) agonist CpG oligodeoxynucleotides are prime candidates for boosting anti-lymphoma immunity, as direct intratumoral injection shows promising anti- tumor effects in both animal and clinical studies. In order to target CpG to all tumor sites in vivo, we adopted an antibody conjugation technique we recently described to achieve direct chemical linkage of CpG to the anti-CD20 antibody rituximab. Remarkably, the antibody-CpG conjugate was able to reproducibly eradicate established tumors from 100% of mice bearing a highly aggressive, rituximab- resistant human CD20+ B cell lymphoma. We thus propose the following aims to characterize the activity, mechanisms of action, and clinically-relevant translational principles for antibody-CpG conjugates against B cell lymphomas: Aim 1. Evaluate the efficacy of novel rituximab-CpG conjugates in syngeneic, immunocompetent mice bearing 2 different murine lymphomas expressing human CD20. Aim 2. Compare the in vivo efficacy of rituximab conjugates containing CpG oligodeoxynucleotides of the functionally distinct A, B, and C classes. Aim 3. Determine the mechanisms of anti-tumor action for rituximab-CpG in syngeneic models, and whether tumor regression leads to secondary adaptive T cell responses against tumor antigens released from dying lymphoma cells. Aim 4. Test rituximab-CpG conjugates against human B cell lymphoma xenografts and primary human lymphoma specimens grown in immunodeficient mice. Aim 5. Explore antibody-CpG conjugates targeting alternative B cell lymphoma surface antigens such as CD19, that internalize upon antibody binding, further broadening the applicability of this approach.

描述（由申请人提供）：抗CD20单克隆抗体（MAB）（例如利妥昔单抗）已成为B细胞非霍奇金淋巴瘤（NHL）治疗中的基石，但仅部分有效，因为大多数患者最终都会复发并保持“无法治疗”。尽管目前的遗传工程和努力正在产生具有增强抗体依赖性细胞毒性（ADCC），补体依赖性细胞毒性（CDC）和促凋亡功能的MAB，但这些改善在很大程度上是渐进的，并且在很大程度上却不会导致MAB可改变肿瘤微生物的不受欢迎的不受欢迎的不受欢迎的不受欢迎的不受欢迎的不受欢迎的不受欢迎的不受欢迎的不受欢迎的势力群体。我们假设可以通过将这些精确的肿瘤靶向车辆与免疫调节物质联系起来在肿瘤微环境中释放来提高抗淋巴瘤mAB的功效。我们的实验室现在已经收集了一套独特的细胞系模型和抗CD20试剂，包括表达人CD20的鼠淋巴瘤，人CD20转基因小鼠和抗毛素CD20 MABS，首次允许对免疫能力宿主中抗CD20疗法进行详细的建模。 Toll样受体9（TLR9）激动剂CpG寡脱氧核苷酸是提高抗淋巴瘤免疫力的主要候选者，因为直接肿瘤内注射显示动物和临床研究都显示出有希望的抗肿瘤作用。为了将CpG靶向体内所有肿瘤部位，我们采用了一种抗体结合技术，我们最近描述的是实现CpG与抗CD20抗体利妥昔单抗的直接化学连接。值得注意的是，抗体-CPG结合物能够从100％带有高度侵略性的利妥昔单抗的人CD20+ B细胞淋巴瘤中重复根除已建立的肿瘤。 We thus propose the following aims to characterize the activity, mechanisms of action, and clinically-relevant translational principles for antibody-CpG conjugates against B cell lymphomas: Aim 1. Evaluate the efficacy of novel rituximab-CpG conjugates in syngeneic, immunocompetent mice bearing 2 different murine lymphomas expressing human CD20. AIM 2。比较含有功能上A，B和C类的CpG寡脱氧核苷酸的利妥昔单抗偶联物的体内功效。 AIM 3。确定合成模型中利妥昔单抗CPG的抗肿瘤作用的机制，以及肿瘤的回归是否导致二次自适应T细胞反应对染上淋巴瘤细胞释放的肿瘤抗原的次级自适应T细胞反应。 AIM 4。针对人类B细胞淋巴瘤异种移植物和原发性人淋巴瘤测试利妥昔单抗CPG结合在免疫缺陷小鼠中生长的原发性淋巴瘤。 AIM 5。探索靶向替代B细胞淋巴瘤表面抗原（例如CD19）的抗体CPG结合物，这些抗体具有内化的抗体结合，进一步拓宽了这种方法的适用性。