Targeting surface b2M for myeloma and bone therapy

靶向表面 b2M 用于骨髓瘤和骨治疗

基本信息

批准号：
8192944
负责人：
Qing Yi
金额：
$ 31.64万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8192944
关键词：
Affect American Antibodies Apoptosis Apoptotic B lymphoid malignancy B-Lymphocytes Blood Cells Bone Diseases Bone Marrow Bone Resorption CD34 gene Cancer Patient Cell Death Cell Line Cell secretion Cells Coculture Techniques Cytostatics Development Dexamethasone Disease Dose Epidermal Growth Factor Receptor Epithelial Goals Growth HLA-A2 Antigen Hematologic Neoplasms Hematopoiesis Hematopoietic Histocompatibility Antigens Class I Hour Human Hypercalcemia Implant In Vitro Interleukin-6 Lead Ligands Lytic Lesion MAPK8 gene MHC Class I Genes Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Proteins Mesenchymal Methods Mitochondria Modeling Monoclonal Antibodies Multiple Myeloma Mus NOD/SCID mouse Neurons Normal Cell Nuclear Organ Osteoclasts Osteoporosis Pathological fracture Patients Pharmaceutical Preparations Phosphotransferases Plasma Cells Protein Binding Proteins Publications Recurrent disease Renal Cell Carcinoma Renal function Reporting Role SCID-hu Mice Safety Series Signal Pathway Stem cells Surface T-Lymphocyte TNF gene TNFSF11 gene Testing Therapeutic Therapeutic Agents Therapeutic Monoclonal Antibodies Tissues Transgenic Organisms Xenograft procedure bone cancer cell caspase-9 cell transformation chemotherapy cytochrome c cytokine fetal in vivo innovation killings leukemia/lymphoma mouse model neoplastic cell novel osteoblast differentiation outcome forecast prevent receptor research study response small molecule spinal cord compression tumor

项目摘要

Multiple myeloma (MM) is still incuable B-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recently made a novel and exciting discovery that anti-beta2-microglobulin (beta2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells in vitro, and were active and therapeutic in vivo in xenograft mouse models of myeloma. Anti-beta2M mAb-induced apoptosis in myeloma cells were not blocked by high concentrations of soluble beta2M, IL-6, or other myeloma growth and survival factors, and was stronger than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-beta2M mAbs may be used as therapeutic agents to treat patients with MM. This hypothesis will be tested by the following aims. Aim 1 will examine the mechanisms of anti-beta2M mAb-induced apoptosis in myeloma cells. Using normal plasma or B cells as controls, we will define the role of surface MHC class I and class I-like molecules in these responses, and examine surface proteins binding to, the downstream kinases, and intracellular signaling and apoptosis pathways induced by anti-beta2M mAbs. Aim 2 will elucidate the mechanism of anti-beta2M mAb-mediated protection of myeloma bone disease, and Aim 3 will develop strategies to enhance the efficacy of anti-beta2M mAbs to induce apoptosis in myeloma cells. These novel studies may lead to the development of anti-beta2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surface beta2M and MHC class I molecules.

多发性骨髓瘤 (MM) 仍然是无法治愈的 B 细胞恶性肿瘤，每年影响超过 14,000 名美国人。即使是当今最积极的治疗方法，骨髓瘤肿瘤细胞也能存活下来，从而导致疾病复发。该项目的长期目标是开发更有效的细胞抑制疗法来根除骨髓瘤细胞。我们最近有了一个令人兴奋的新发现，即抗 β2 微球蛋白 (β2M) 单克隆抗体 (mAb) 在已建立的骨髓瘤细胞系和来自患者的原发性骨髓瘤细胞中都具有很强的凋亡活性。这些单克隆抗体在与正常造血细胞共培养时选择性地靶向并杀死骨髓瘤细胞，而不会在体外损害包括CD34+干细胞在内的正常血细胞，并且在骨髓瘤异种移植小鼠模型中具有活性和治疗作用。抗-β2M mAb 诱导的骨髓瘤细胞凋亡不会被高浓度的可溶性 β2M、IL-6 或其他骨髓瘤生长和生存因子阻断，并且比目前用于治疗 MM 的化疗药物（例如地塞米松）观察到的凋亡更强。）。 mAb 通过抑制 PI3K/Akt 和 ERK、激活 JNK 并损害线粒体完整性来诱导细胞死亡，从而导致细胞色素 c 释放和 caspase-9 依赖性级联的激活。此外，我们还表明单克隆抗体可以预防或减缓患者的骨质破坏。因此，我们假设抗 β2M mAb 可用作治疗 MM 患者的治疗剂。该假设将通过以下目标进行检验。目标 1 将研究抗-β2M mAb 诱导骨髓瘤细胞凋亡的机制。使用正常血浆或 B 细胞作为对照，我们将定义表面 MHC I 类和 I 类样分子在这些反应中的作用，并检查与下游激酶结合的表面蛋白，以及由抗-细胞因子诱导的细胞内信号传导和凋亡途径。 beta2M 单克隆抗体。目标 2 将阐明抗 β2M mAb 介导的骨髓瘤骨病保护机制，目标 3 将制定策略以增强抗 β2M mAb 诱导骨髓瘤细胞凋亡的功效。这些新研究可能会导致抗β2M mAbs的开发，作为第一个临床上有用且有效的治疗性mAbs，用于治疗多发性骨髓瘤和表达表面β2M和MHC I类分子的其他潜在恶性肿瘤。