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

多发性骨髓瘤(MM)仍然是一种无法治愈的B细胞恶性肿瘤，每年影响超过14,000名美国人。 骨髓瘤细胞即使在当今最激进的治疗方法下也能存活下来，从而导致疾病。 旧病复发。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。我们最近有了一个新的令人兴奋的发现，即抗p2-微球蛋白(P2m) 单抗在已建立的骨髓瘤细胞系和骨髓瘤细胞系中都具有很强的凋亡活性 来自患者的原代骨髓瘤细胞。单抗在与骨髓瘤细胞共培养时选择性靶向并杀伤骨髓瘤细胞 正常的造血细胞而不损害正常的血细胞，包括CD34+干细胞。抗p2M单抗Abduced 可溶性p2M(10-100 ng/mL，高3-30倍)不能阻断骨髓瘤细胞的凋亡 与大多数MM患者相比，后者约为3JAG/mL)、IL-6或其他骨髓瘤生长和生存因子。 单抗通过抑制P13K/Akt和ERK，激活JNK，并妥协而诱导细胞死亡 线粒体的完整性，导致细胞色素c的释放和激活依赖于caspase-9的级联反应。 此外，该单抗在异种骨髓瘤模型小鼠体内也具有活性和治疗作用。 因此，我们假设抗p2M单抗可能被用作治疗MM患者的药物。这一假设将通过以下目的进行验证。目的1探讨抗p2M单抗诱导骨髓瘤细胞凋亡的机制。以正常血浆或B细胞为对照，我们将确定表面MHC I类和L类分子在这些反应中的作用，并检测表面蛋白与下游激酶的结合，以及抗p2M单抗诱导的细胞内信号和凋亡途径。Aim 2将利用免疫效应细胞或分子来增强抗p2M单抗的疗效，Aim 3将开发与新型抗骨髓瘤药物相结合的策略来增强抗p2M单抗诱导骨髓瘤细胞凋亡的效力，Aim 4将进行临床前和临床研究以检验单抗的安全性和毒性。

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.