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，预后极差。迫切需要新的有效治疗PCa的方法。放射免疫疗法（RIT）依赖于抗原-抗体结合以向肿瘤细胞递送细胞毒性剂量的α或β辐射。RIT已成功用于治疗难治性和复发性淋巴瘤，两种放射性标记的单克隆抗体（mAb）靶向CD 20（Zevalin（R）和Bexxar（R））。最近FDA批准Zevalin作为新诊断的非霍奇金淋巴瘤（NHL）患者的一线治疗。与许多其他治疗方式相比，RIT的力量在于当从mAb发出的颗粒辐射引起细胞的物理破坏时其杀细胞性质。此外，RIT具有良好的安全性记录，其副作用比常规化疗少得多，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的PCa患者中均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，需要新的靶向抗原和更强大的放射性核素的选择，使RIT成功治疗PCa。靶向细胞内抗原（IntA）是由A. Epstein作为RIT中靶向表面抗原的替代方案。由于快速的细胞更新，IntA在侵袭性生长的肿瘤中变得易于与mAb结合。这种方法的优点是针对IntA的mAb与健康组织上的表面抗原具有非常低的交叉反应性，这导致治疗的高特异性和低毒性。这种方法目前正在临床上进行测试-Epstein博士正在晚期肺癌患者中进行放射性标记的核内组蛋白mAb的临床试验;而Dadachova博士的小组正在转移性黑色素瘤患者中使用放射性标记的黑色素结合mAb靶向黑色素。我们假设，通过用α粒子212-铅/212-铋（212 Pb/212 Bi）的体内发生器放射性标记的特异性mAb靶向PCa中的核内组蛋白，我们将能够向肿瘤递送高的杀肿瘤剂量，而对正常组织没有毒性。我们还假设，通过用化疗剂如顺铂或吉西他滨预处理肿瘤，我们将使一些肿瘤细胞无活力，从而使更多的核内组蛋白可用于放射性标记的特异性mAb，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核内组蛋白单克隆抗体对PCa的系统治疗。如果成功，这种方法提供了治愈PCa的可能性。 公共卫生相关性：该项目提出了用放射性标记的核内组蛋白mAb研究PCa的全身治疗，并采用了一种新的想法，即用特异性mAb靶向侵袭性快速生长的PCa中的核内抗原，并结合强大的α粒子发射体内放射性核素发生器212 Pb/212 Bi。如果成功，这种方法提供了治愈PCa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.