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：
8408799
负责人：
Qing Yi
金额：
$ 8.88万
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 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8408799
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）仍然是不可能的B细胞恶性肿瘤，每年影响14,000多名美国人。骨髓瘤肿瘤细胞甚至可以在当今可用的最具侵略性的治疗中生存，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消除骨髓瘤细胞。最近，我们做出了一个新颖而令人兴奋的发现，即抗BETA2-微球蛋白（betA2M）单克隆抗体（mAb）在已建立的骨髓瘤细胞系和患者的原发性骨髓瘤细胞中均具有强大的凋亡活性。 mAb选择性地靶向并杀死与正常造血细胞共培养中的骨髓瘤细胞，而不会损害正常血细胞，包括在体外CD34+干细胞，并且在骨髓瘤的异种移植小鼠模型中具有活性和治疗性。抗BETA2M MAB诱导的骨髓瘤细胞凋亡不会被高浓度的可溶性β2M，IL-6或其他骨髓瘤的生长和生存因子阻塞，并且比目前用于用于当前用于MM的化学疗法药物的凋亡更强（例如，脱氧症患者）。 mAb通过抑制PI3K/AKT和ERK诱导细胞死亡，激活JNK和损害线粒体完整性，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，MAB可以防止患者的骨骼破坏或放缓。因此，我们假设抗β2MmAB可以用作治疗MM患者的治疗剂。该假设将通过以下目标进行检验。 AIM 1将检查抗β2MmAb诱导的骨髓瘤细胞凋亡的机制。使用正常的血浆或B细胞作为对照，我们将定义表面MHC I类和类似I类的分子在这些反应中的作用，并检查与抗BETA2M MAB诱导的结合，下游激酶以及细胞内信号传导和细胞内信号传导和细胞内信号传导和凋亡途径。 AIM 2将阐明抗BETA2M MAB介导的骨瘤骨病的保护的机理，AIM 3将制定策略，以增强抗β2MMAB的功效，以诱导骨髓瘤细胞凋亡。这些新的研究可能导致抗β2MmAB的发展，作为第一个用于治疗MM和其他可能表达表面表面β2M和MHC I类分子的恶性肿瘤的临床有效和有效的治疗单元。