BioDrugs. 2003;17(4):290-5. doi: 10.2165/00063030-200317040-00009.
Iodine-131 tositumomab [B1, Bexxar , iodine-131 anti-B1 antibody] is a murine antibody conjugated to iodine 131 that recognises and binds to the B1 (CD20) antigen which is found specifically on B lymphocytes. Iodine-131 tositumomab has a dual mechanism of action. It is capable of initiating a host immune response to those B cells to which it is attached, and it also triggers apoptosis in a significant proportion of the cells to which it binds. The product was first discovered by Coulter Corporation, Miami, in collaboration with the Dana-Farber Cancer Institute and the University of Michigan. The spin-off company Coulter Pharmaceutical, upon its formation, obtained worldwide rights to iodine-131 tositumomab. (Coulter Corporation was acquired subsequently by Beckman Instruments in October 1997. The union of the two companies produced Beckman Coulter.) In December 2000, Coulter Pharmaceutical was acquired by, and merged into, Corixa Corporation.Iodine-131 tositumomab is available for licencing in Japan. Corixa Corporation and GlaxoSmithKline signed an agreement to jointly develop and commercialise iodine-131 tositumomab. The total agreement has a potential value of up to $US132 million, plus shared profits and royalties. The two companies will jointly market the antibody in the US following regulatory approval. Corixa Corporation has announced it expects iodine-131 tositumomab to be approved in the US for non-Hodgkin's lymphoma (NHL). Under the terms of the original agreement, GlaxoSmithKline will receive exclusive marketing rights outside the US, excluding Japan. However, an amended agreement between the two companies will allow Corixa Corporation to also market the product outside the US. In February 2003, the European Commission granted iodine-131 tositumomab orphan-drug designation. Corixa Corporation and GlaxoSmithKline also intend to jointly investigate the use of the product in other indications. GlaxoSmithKline may also receive access to second generation anti-CD20 compounds under its agreement with Corixa Corporation. In May 2003, Corixa Corporation entered into an agreement that will see GlaxoSmithKline market Bexxar in Canada. Under the terms of the agreement, Corixa Corporation will manufacture and supply the product to GlaxoSmithKline, who will register, market and sell it in Canada. In October 2001, Amersham PLC, a supplier of medical equipment, announced that its Amersham Health unit had signed a marketing agreement with Corixa Corporation. The agreement allows Amersham Health to market iodine-131 tositumomab in Europe. Corixa Corporation formed agreements with Boehringer Ingelheim Pharma KG and Lonza Biologics to produce the B1 antibody and radiolabelling of the antibody has been contracted out to MDS Nordion.Iodine-131 tositumomab has received orphan drug and fast track designation for the treatment of NHL. Corixa Corporation submitted a Biologics Licence Application (BLA) to the US FDA in 1999, seeking permission to market Bexxar in the US for the treatment of relapsed or refractory, low grade or transformed low grade B-cell NHL. Following a priority review, the US FDA requested that Corixa Corporation reformat certain sections and perform additional analyses of existing data in its BLA. Corixa Corporation and GlaxoSmithKline resubmitted their BLA to the US FDA in September 2000. The BLA was subsequently accepted by the US FDA in November 2000. However, in March 2001, the US FDA requested additional information in its complete review letter to Corixa Corporation and marketing partner GlaxoSmithKline. The two companies submitted data pertaining to the chemistry, manufacturing and controls section of the BLA, and to the majority of the questions regarding the clinical section of the BLA in August 2001. Corixa Corporation and GlaxoSmithKline submitted the remainder of the response to the US FDA in September 2001, following an independent review of clinical trial data. In March 2002, Corixa Corporation received another complete review letter from the US FDA, which stated that additional clinical trials would have to be conducted in order to provide adequate evidence of the safety and clinical benefit of Bexxa. The US FDA also denied Corixa Corporation's request for accelerated approval, stating that the data provided was inadequate to show that Bexxar filled an unmet medical need. Corixa Corporation has met formally with the US FDA but the two were unable to resolve their differences. Corixa Corporation will now file a formal request for dispute resolution under the Food and Drug Administration Modernisation Act. Corixa Corporation also requested a presentation of Bexxa data to the US FDA's scientific advisors. In June 2002, the US FDA granted the company's appeal for additional regulatory review. In December 2002, the US FDA's Oncologic Drugs Advisory Committee agreed that Bexxar has clinical benefit for patients with NHL. In May 2003, Corixa Corporation and GlaxoSmithKline announced that they had fulfilled many of the steps required for US FDA approval, however the US FDA has extended its review of the application for another 3 months. This extension will allow for further refinement of post marketing commitments and package insert language, and to ensure they are consistent with an updated safety database requested by the US FDA and submitted by Corixa Corporation in early April. GlaxoSmithKline was waiting for the outcome of the situation before deciding on marketing plans for Bexxar. Corixa Corporation and GlaxoSmithKline will conduct a head-to-head study of Bexxar and Idec's Zevalin, planned for mid-2003. The trial will likely be one of three phase IV studies that the US FDA requires for accelerated approval of Bexxar. Corixa Corporation initiated its Expanded Access Program for Bexxar in response to requests from physicians and patients for continued access to Bexxar during the period prior to potential US FDA marketing approval.A phase II multicentre trial of Bexxar in combination with CHOP chemotherapy is underway in the US as first-line therapy in patients with intermediate-grade NHL. Corixa Corporation has initiated a phase II trial of iodine-131 tositumomab in combination with cyclophosphamide, vincristine and prednisone for the treatment of previously untreated low-grade NHL. The trial was initiated while the company was preparing its BLA for Bexxar for use as a single agent for relapsed or refractory NHL. Corixa Corporation intends to pursue additional trials to expand the potential use of iodine-131 tositumomab to other indications, including chronic lymphocytic leukaemia. The agent is also in a clinical trial for preparation in autologous bone marrow transplant patients. The trial is designed to test the combination of iodine-131 tositumomab and chemotherapy. The trial began in 1995 and has so far enrolled 40 patients. In addition, a phase II dose-escalation trial has begun at the University of Nebraska for the combined use of iodine-131 tositumomab and chemotherapy as preparation for autologous bone marrow transplant. Corixa Corporation has received an issued US patent covering methods for administering and dosing radioimmunotherapy for the treatment of B-cell lymphomas. The patent covers iodine-131 tositumomab and other anti-CD20 antibodies used to aid in selective tumour targeting. Corixa Corporation has exclusive rights to the patent.A February 2000 media release from GlaxoSmithKline and Corixa Corporation stated that they had been issued a composition patent relating to radiolabelled monoclonal antibodies (including Bexxar) for the treatment of B-cell lymphomas. On 11 September 2001, IDEC announced that it had filed two separate lawsuits. The first lawsuit is against Corixa Corporation and the University of Michigan on six patents pertaining to products and processes related to radioimmunotherapy. They seek a declaration that Zevalin does not infringe Corixa Corporation's issued US patents. The second lawsuit involves two patents relating to cell culture media, and is against GlaxoSmithKline. IDEC's lawsuit in this case, seeks a declaration that its manufacture of Zevalin does not infringe GlaxoSmithKline's issued US patents. Corixa Corporation and GlaxoSmithKline have also filed a complaint for patent infringement against IDEC. These actions however, should have no effect on the regulatory process that Zevalin is completing, or prevent IDEC from launching the drug before iodine-131 tositumomab.A year earlier, in March 2001, the Financial Times reported that Bexxar could reach peak sales of $US120 million. In 1998, Coulter Pharmaceutical received a licencee fee payment of $US34 million from SmithKline Beecham (now GSK) in the fourth quarter of the year, as part of the joint development and commercialisation agreement for Bexxar.
碘-131托西莫单抗[B1，Bexxar，碘-131抗B1抗体]是一种与碘131偶联的鼠源抗体，可识别并结合特异性存在于B淋巴细胞上的B1（CD20）抗原。碘-131托西莫单抗具有双重作用机制。它能够引发宿主对其所附着的B细胞的免疫反应，还能在很大比例的与其结合的细胞中触发凋亡。该产品最初由迈阿密的库尔特公司与达纳-法伯癌症研究所及密歇根大学合作发现。衍生公司库尔特制药成立后，获得了碘-131托西莫单抗的全球权利。（库尔特公司随后于1997年10月被贝克曼仪器公司收购。两家公司合并后成立了贝克曼库尔特公司。）2000年12月，库尔特制药被科里克斯公司收购并并入该公司。碘-131托西莫单抗在日本可供授权使用。科里克斯公司与葛兰素史克公司签署了一项协议，共同开发碘-131托西莫单抗并将其商业化。整个协议的潜在价值高达1.32亿美元，外加共享利润和版税。两家公司将在美国监管批准后联合在美国市场销售该抗体。科里克斯公司宣布，预计碘-131托西莫单抗将在美国获批用于治疗非霍奇金淋巴瘤（NHL）。根据原协议条款，葛兰素史克将获得美国以外地区（不包括日本）的独家营销权。然而，两家公司修订后的协议将允许科里克斯公司也在美国以外地区销售该产品。2003年2月，欧盟委员会授予碘-131托西莫单抗孤儿药认定。科里克斯公司和葛兰素史克公司还打算联合研究该产品在其他适应症中的应用。葛兰素史克公司根据与科里克斯公司的协议，可能还会获得第二代抗CD20化合物的使用权。2003年5月，科里克斯公司达成一项协议，将由葛兰素史克公司在加拿大销售Bexxar。根据协议条款，科里克斯公司将生产并向葛兰素史克公司供应该产品，葛兰素史克公司将在加拿大进行注册、营销和销售。2001年10月，医疗设备供应商阿美施公司宣布，其阿美施健康部门已与科里克斯公司签署了一项营销协议。该协议允许阿美施健康在欧洲销售碘-131托西莫单抗。科里克斯公司与勃林格殷格翰制药股份公司和龙沙生物制品公司达成协议，生产B1抗体，并已将抗体的放射性标记外包给MDS Nordion公司。碘-131托西莫单抗已获得治疗NHL的孤儿药和快速通道认定。科里克斯公司于1999年向美国食品药品监督管理局（FDA）提交了生物制品许可申请（BLA），寻求在美国市场销售Bexxar用于治疗复发或难治性、低度或转化型低度B细胞NHL。经过优先审评后，美国FDA要求科里克斯公司重新编排某些部分，并对其BLA中的现有数据进行额外分析。科里克斯公司和葛兰素史克公司于2000年9月再次向美国FDA提交了BLA。该BLA随后于2000年11月被美国FDA接受。然而，2001年3月，美国FDA在给科里克斯公司和营销合作伙伴葛兰素史克公司的完整审评信中要求提供更多信息。两家公司于2001年8月提交了与BLA的化学、生产和控制部分相关的数据，以及与BLA临床部分的大多数问题相关的数据。在对临床试验数据进行独立审评后，科里克斯公司和葛兰素史克公司于2001年9月向美国FDA提交了其余的回复。2002年3月，科里克斯公司收到美国FDA的另一封完整审评信，信中指出必须进行更多的临床试验，以提供足够的证据证明Bexxa的安全性和临床益处。美国FDA还驳回了科里克斯公司加速批准的请求，称所提供的数据不足以表明Bexxar满足了未满足的医疗需求。科里克斯公司已与美国FDA进行了正式会面，但双方未能解决分歧。科里克斯公司现在将根据《食品药品管理现代化法案》提出正式的争议解决请求。科里克斯公司还请求向美国FDA的科学顾问介绍Bexxa的数据。2002年6月，美国FDA批准了该公司的额外监管审评请求。2002年12月，美国FDA的肿瘤药物咨询委员会一致认为Bexxar对NHL患者具有临床益处。2003年5月，科里克斯公司和葛兰素史克公司宣布，他们已经完成了美国FDA批准所需的许多步骤，然而美国FDA将其对该申请的审评延长了3个月。此次延期将允许进一步完善上市后承诺和药品说明书内容，并确保它们与美国FDA要求并由科里克斯公司于4月初提交的更新后的安全数据库一致。葛兰素史克公司在决定Bexxar的营销计划之前，正在等待这一情况的结果。科里克斯公司和葛兰素史克公司计划于2003年年中对Bexxar和Idec公司的泽瓦林进行头对头研究。该试验可能是美国FDA要求加速批准Bexxar所需的三项IV期研究之一。应医生和患者在Bexxar可能获得美国FDA上市批准之前继续使用该药物的请求，科里克斯公司启动了Bexxar的扩大使用计划。在美国，一项Bexxar联合CHOP化疗作为中度NHL患者一线治疗的II期多中心试验正在进行。科里克斯公司已启动一项碘-131托西莫单抗联合环磷酰胺、长春新碱和泼尼松治疗既往未治疗的低度NHL的II期试验。该试验是在公司为将Bexxar作为复发或难治性NHL的单一药物准备BLA时启动的。科里克斯公司打算进行更多试验，以扩大碘-131托西莫单抗在其他适应症中的潜在用途，包括慢性淋巴细胞白血病。该药物也正在进行一项针对自体骨髓移植患者预处理的临床试验。该试验旨在测试碘-131托西莫单抗与化疗的联合应用。该试验于1995年开始，迄今为止已招募了40名患者。此外，内布拉斯加大学已开始一项II期剂量递增试验，用于联合使用碘-131托西莫单抗和化疗作为自体骨髓移植的预处理。科里克斯公司已获得一项已发布的美国专利，涵盖用于治疗B细胞淋巴瘤进行放射免疫治疗的给药和剂量方法。该专利涵盖碘-131托西莫单抗和其他用于辅助选择性肿瘤靶向的抗CD20抗体。科里克斯公司拥有该专利的独家权利。葛兰素史克公司和科里克斯公司2000年2月的一份新闻稿称，他们已获得一项与用于治疗B细胞淋巴瘤的放射性标记单克隆抗体（包括Bexxar）相关的组合物专利。2001年9月11日，Idec公司宣布已提起两起单独诉讼。第一起诉讼是针对科里克斯公司和密歇根大学，涉及六项与放射免疫治疗相关的产品和工艺专利。他们寻求宣告泽瓦林不侵犯科里克斯公司已发布的美国专利。第二起诉讼涉及两项与细胞培养基相关的专利，被告是葛兰素史克公司。Idec公司在本案中的诉讼寻求宣告其生产泽瓦林不侵犯葛兰素史克公司已发布的美国专利。科里克斯公司和葛兰素史克公司也对Idec公司提起了专利侵权投诉。然而，这些行动不应影响泽瓦林正在完成的监管程序，也不应阻止Idec公司在碘-131托西莫单抗之前推出该药物。一年前，即2001年3月，英国《金融时报》报道称，Bexxar的峰值销售额可能达到1.2亿美元。1998年，库尔特制药在当年第四季度从史克必成（现为葛兰素史克）获得了3400万美元的许可费支付，这是Bexxar联合开发和商业化协议的一部分。
