P2 - ANTI-B2-MICR0GL0BULIN ANTIBODIES AS THERAPEUTIC AGENTS FOR MULTIPLE MYELOMA

P2 - 抗-B2-MICR0GL0BULIN 抗体作为多发性骨髓瘤的治疗剂

• 批准号: 8728775
• 负责人: Qing Yi
• 金额: $ 17.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728775
• 关键词: Affect; American; Antibodies; Apoptosis; Apoptotic; B lymphoid malignancy; B-Lymphocytes; Biological; Blood; Blood Cells; CD34 gene; Cancer Center; Cancer Patient; Cell Death; Cell Line; Cells; Clinical Research; Coculture Techniques; Complement; Cytostatics; Development; Drug Kinetics; Drug resistance; Effector Cell; Epithelial; Goals; Growth; HLA-A2 Antigen; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Histocompatibility Antigens Class I; Hour; Human; Immune; Immunoglobulin G; Interleukin-6; Lead; MAPK8 gene; MHC Class I Genes; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane Proteins; Mitochondria; Modeling; Molecular Target; Monoclonal Antibodies; Mononuclear; Multiple Myeloma; Mus; Natural Killer Cells; Neurons; Normal Cell; Organ; Osteoclasts; Patients; Peptides; Pharmaceutical Preparations; Phosphotransferases; Physiological; Plasma Cells; Protein Binding; Proteins; Publications; Recurrent disease; Renal Cell Carcinoma; Renal function; Reporting; Role; SCID-hu Mice; Safety; Signal Pathway; Stem cells; Surface; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Monoclonal Antibodies; Tissues; Toxic effect; Toxicology; Transgenic Organisms; Xenograft procedure; cancer cell; caspase-9; cell transformation; chemotherapy; crosslink; cytochrome c; design; in vivo; invariant chain; killings; leukemia/lymphoma; mouse model; neoplastic cell; novel; outcome forecast; pre-clinical; preclinical study; receptor; response; small molecule; success; tumor

Multiple myeloma (MM) is still incurable 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 recentiy made a novel and exciting discovery that anti-p2-microglobulin (P2M) 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. Anti-p2M mAbinduced apoptosis in myeloma cells were not blocked by soluble p2M (10-100 ng/mL, 3- to 30-fold higher than that in most MM patients, which are about 3 jag/mL), IL-6, or other myeloma growth and survival factors. The mAbs induced cell death via inhibiting P13K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Furthermore, the mAbs were also active and therapeutic in vivo in xenograft mouse models of myeloma. Thus, we hypothesize that anti-p2M 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-p2M mAbinduced apoptosis in myeloma cells. Using normal plasma or B cells as controls, we will define the role of surface MHC class I and class l-like molecules in these responses, and examine surface proteins binding to, the downstream kinases, and intracellular signaling and apoptosis pathways induced by anti-p2M mAbs. Aim 2 will utilize immune effector cells or molecules to enhance the efficacy of anti-p2M mAbs, Aim 3 will develop strategies to enhance the efficacy of anti-p2M mAbs to induce apoptosis in myeloma cells by combining with novel antimyeloma agents, and Aim 4 will perform pre-clinical and clinical studies to examine the safety and toxicity profiles of the mAbs.

多发性骨髓瘤（MM）仍无法治愈，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，导致疾病 复发。该项目的长期目标是开发更有效的细胞固化疗法以消除 骨髓瘤细胞。我们最近做出了一个小说而令人兴奋的发现，即抗P2-微球蛋白（P2M） 单克隆抗体（mAb）在建立的骨髓瘤细胞系和 来自患者的原发性骨髓瘤细胞。 mAb选择性地靶向并杀死与 正常的造血细胞而不会损害正常血细胞，包括CD34+干细胞。抗P2M示意 可溶性P2M（10-100 ng/mL，3至30倍高的骨髓瘤细胞凋亡都不会阻塞 在大多数MM患者中，大约3个JAG/mL），IL-6或其他骨髓瘤生长和生存因子。 mAb通过抑制p13k/akt和erk诱导细胞死亡，激活JNK并妥协 线粒体完整性，导致细胞色素c释放和caspase-9依赖性级联反应的激活。 此外，在异种移植小鼠的骨髓瘤模型中，mAb在体内也具有活性和治疗性。 因此，我们假设抗P2M mAB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P2M抗骨髓瘤细胞凋亡的机理。我们将使用正常的血浆或B细胞作为对照，我们将定义表面MHC I类和L类分子在这些反应中的作用，并检查与抗P2M MAB诱导的与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的作用。 AIM 2将利用免疫效应细胞或分子增强抗P2M MAB的功效，AIM 3将制定策略，以增强抗P2M MAB的功效来诱导骨髓瘤细胞的凋亡，通过与新型抗氧化剂瘤药物相结合，AIM 4将对临床和临床研究进行术前和临床研究的效率，并具有毒性的毒性和毒性的效率。