Targeted therapy of pancreatic cancer with in vivo radionuclide generator

描述(申请人提供)：胰腺癌(PCa)是最致命的癌症之一，预后非常差。迫切需要治疗前列腺癌的新的有效方法。放射免疫治疗(RIT)依赖于抗原-抗体结合，将细胞毒性剂量的α或β辐射传递给肿瘤细胞。RIT已成功地用于治疗难治性和复发性淋巴瘤，两种针对CD20的放射性标记单抗(Zvalin(R)和Bexxar(R))已被成功地用于治疗。最近，FDA批准齐瓦林作为新诊断的非霍奇金淋巴瘤(NHL)患者的一线治疗药物。与许多其他治疗方法相比，RIT的强大之处在于，当mAbs发出的微粒辐射导致细胞物理破坏时，RIT具有杀细胞的性质。此外，RIT有很好的安全记录，副作用比传统化疗少得多，而且不受多药耐药机制的影响。然而，在PCa中，RIT在临床前和不能切除的PCa患者中都显示出非常有限的结果。RIT不能在PCA中提供持续反应的原因可能是靶向抗原和放射性核素的错误选择。显然，需要新的靶向抗原的选择和更强大的放射性核素来使RIT在治疗PCa方面取得成功。靶向细胞内抗原(Intas)由A·爱泼斯坦博士率先提出，作为RIT中靶向表面抗原的替代方法。由于快速的细胞周转，在侵袭性生长的肿瘤中，由于细胞的快速周转，INTA变得可以与mAb结合。这种方法的优点是抗Intas的单抗与健康组织表面抗原的交叉反应性很低，从而导致治疗的高特异性和低毒性。这一方法目前正在临床上进行测试--爱泼斯坦博士正在进行一项针对晚期肺癌患者核内组蛋白的放射性标记单抗的临床试验；而达达乔娃博士的团队则在转移性黑色素瘤患者中使用放射性标记黑色素结合单抗进行靶向治疗。我们推测，通过用放射性标记的强大的体内α粒子发生器212-铅/212-铋(212-铅/212-铋)的特异性mAb靶向PCA的核内组蛋白，我们将能够向肿瘤输送高剂量的杀瘤药物，而不会对正常组织产生毒性。我们还假设，通过用顺铂或吉西他滨等化疗药物预治疗肿瘤，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被放射性标记的特异性单抗获得，这将导致肿瘤摄取的增加和更好的治疗效果。该项目建议研究核内组蛋白的放射性标记单抗对前列腺癌的系统治疗。如果成功，这种方法提供了治愈前列腺癌的可能性。 公共卫生相关性：该项目建议研究放射性标记单抗对核内组蛋白的系统治疗，并采用一种新的想法，即在侵袭性快速生长的PCa中使用特定单抗靶向核内抗原，并结合体内强大的放射性核素产生器212Pb/212Bi。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.