Targeted therapy of pancreatic cancer with in vivo radionuclide generator

描述（由申请人提供）：胰腺癌（PCa）是最致命的癌症之一，预后非常差。迫切需要新的有效的治疗前列腺癌的方法。放射免疫疗法（RIT）依靠抗原-抗体结合向肿瘤细胞提供细胞毒性剂量的α或β辐射。RIT已成功用于治疗难治性和复发性淋巴瘤，其两种靶向CD20的放射性标记单克隆抗体(Zevalin（R)和Bexxar(R)）。最近FDA批准泽伐林作为新诊断的非霍奇金淋巴瘤（NHL）患者的一线治疗药物。与许多其他治疗方式相比，RIT的力量在于它的细胞杀伤性质，当单克隆抗体发出的颗粒辐射引起细胞的物理破坏时。此外，RIT具有良好的安全性记录，副作用比传统化疗少得多，并且不受多药耐药机制的影响。然而，在PCa中，RIT在临床前和不可切除PCa患者中都显示出非常温和的结果。RIT不能在PCa中提供持续应答的原因可能是由于靶向抗原和放射性核素的错误选择。显然，为了使RIT成功治疗PCa，需要新的靶向抗原选择和更强的放射性核素。靶向细胞内抗原（IntAs）是由A. Epstein博士首创的，作为RIT中靶向表面抗原的替代方法。由于快速的细胞周转，在恶性生长的肿瘤中，IntAs可以与mAb结合。这种方法的优点是，针对IntAs的单克隆抗体与健康组织表面抗原具有非常低的交叉反应性，从而导致高特异性和低毒性的治疗。这种方法目前正在临床试验中——Epstein博士正在对晚期肺癌患者进行放射性标记的核内组蛋白单抗的临床试验；而达达乔瓦博士的研究小组正在用放射标记的黑色素结合单抗（melanoma -binding mAb）治疗转移性黑色素瘤患者。我们假设，通过使用具有强大体内α粒子发生器212-铅/212-铋（212Pb/212Bi）的特异性单抗靶向前列腺癌的核内组蛋白，我们将能够向肿瘤提供高剂量的杀瘤剂，而不会对正常组织产生毒性。我们还假设，通过使用顺铂或吉西他滨等化疗药物对肿瘤进行预处理，我们将使一些肿瘤细胞无法存活，从而使更多的核内组蛋白可用于放射标记的特异性单抗，这将导致肿瘤摄取增加和更好的治疗结果。该项目建议研究用放射性标记的单克隆抗体对核内组蛋白的系统性治疗。如果成功，这种方法提供了治愈前列腺癌的可能性。

DESCRIPTION (provided by applicant): Pancreatic cancer (PCa) is one of the deadliest cancers with very poor prognosis. New effective methods for therapy of PCa are urgently needed. Radioimmunotherapy (RIT) relies on antigen-antibody binding to deliver cytotoxic doses of alpha- or beta radiation to tumor cells. RIT has been successfully used to treat refractory and recurrent lymphomas, with two radiolabeled monoclonal antibodies (mAb) targeted against CD20 (Zevalin(R) and Bexxar(R)). Very recently FDA has approved Zevalin as a first-line therapy for newly diagnosed patients with non-Hodgkin lymphoma (NHL). The power of RIT in comparison with many other therapeutic modalities is its cytocidal nature when particulate radiation emanating from the mAbs causes physical destruction of the cell. In addition, RIT has excellent safety record having much less side effects than conventional chemotherapy and is not a subject to multidrug resistance mechanisms. However, in PCa RIT has shown very modest results both pre-clinically and in patients with unresectable PCa. The reasons for RIT not being able to deliver sustained responses in PCa may be due to the wrong choices of targeted antigens and radionuclides. Obviously, new choices of targeted antigens and more powerful radionuclides are needed to make RIT successful in treatment of PCa. Targeting of intracellular antigens (IntAs) was pioneered by Dr. A. Epstein as an alternative to targeting surface antigens in RIT. IntAs become accessible for mAb binding in aggressively growing tumors as a result of fast cellular turnover. The advantage of this approach is that mAbs to IntAs have very low cross-reactivity with surface antigens on healthy tissue which leads to high specificity and low toxicity of treatment. This approach is currently is tested in the clinic - Dr. Epstein is conducting a clinical trial of radiolabeled mAb to intranuclear histones in patients with advanced lung cancer; while Dr. Dadachova's group is targeting melanin pigment with radiolabeled melanin-binding mAb in patients with metastatic melanoma. We hypothesize that by targeting intranuclear histones in PCa with specific mAb radiolabeled with powerful in vivo generator of alpha-particles 212-Lead/212-Bismuth (212Pb/212Bi) - we will be able to deliver high tumoricidal doses to the tumors without toxicity to normal tissues. We also hypothesize that by pre-treating tumors with chemotherapeutic agents such as cisplatin or gemcitabine - we will make some tumor cells non-viable thus making more of the intranuclear histones accessible for radiolabeled specific mAb which should result in increased tumor uptake and better therapy results. The project proposes to investigate the systemic treatment of PCa with radiolabeled mAbs to intranuclear histones. If successful, this approach offers the possibility of cure for PCa. PUBLIC HEALTH RELEVANCE: The project proposes to investigate the systemic treatment of PCa with radiolabeled mAbs to intranuclear histones and employs a novel idea of targeting intranuclear antigens with specific mAbs in aggressive fast growing PCa in combination with powerful alpha-particle emitting in vivo radionuclide generator 212Pb/212Bi. If successful, this approach offers the possibility of cure for PCa.