Radioimmunotherapy: An Anti-Neoplastic Strategy

描述（由申请人提供）：尽管III期上皮性卵巢癌（EOC）术后一线化疗的应答率很高，但5Y DFS率很少超过15%。超过50%经剖腹手术证实完全缓解的患者会复发。显然，我们需要更有效的治疗方法！由于无法控制腹内疾病仍然是主要问题，因此对使用腹腔内放射标记抗体（IP）产生了相当大的兴趣。一些研究（包括我们的研究）在EOC中靶向肿瘤相关抗原TAG-72的IP已经显示出令人鼓舞的结果。CC49是第二代小鼠(m)抗tag -72抗体，其亲和力常数比原始抗tag -72抗体B72.3高6倍，在胸腺小鼠中使用人异种移植物的肿瘤：血比比B72.3高16倍。mCC49的免疫原性、较长的半衰期（50h）以及嵌合或cdr移植版本的预计更长的半衰期，导致了针对缺失不同部分的人源化研究，以寻找低免疫原性和半衰期在15-40h范围内的构建体。缺失CH2区域的人源化CC49 （HuCC49ACH2）符合标准。临床前研究表明，HuCC49ACH2的血浆清除率比HuCC49快，肿瘤与正常组织的比值高于HuCC49。因此，预计HuCC49ACn2具有降低的免疫原性（人源化版本），保留完整抗体的二聚体结合位点，并且在人体内循环时间相对较短。我们的IV 131I-HuCC49ACH2在转移性结直肠癌患者中的试点/ I期研究显示，血浆T1/2为20 +/- 3h，与我们之前的mCC49数据相比，前者的T1/2为50 +/- 1h。所有患者至少有一个已知肿瘤部位放射免疫显像阳性，免疫原性低。因此，对于局限于腹腔（+/-腹膜后淋巴结）的复发或原发性难治性EOC患者，我们将：确定IP l31I-HuCC49ACH2的最大耐受剂量及其毒性谱；测定HuCC49ACH2给药IP的血浆药代动力学、全身生物分布、剂量学和结合稳定性；在给定的IP下，描述人类对131I-HuCC49ACn2的免疫反应；作为次要终点，我们将监测抗肿瘤效果。后续试验将是一项II期研究，以确定131I-HuCC49ACH2在耐药/难治性EOC患者中的疗效。

DESCRIPTION (provided by applicant): Despite high response rates to first-line chemotherapy after surgery for stage III epithelial ovarian cancer (EOC), the 5Y DFS rate rarely exceeds 15%. More than 50% of the patients with a laparotomy-confirmed complete response will relapse. Clearly, more effective therapy is needed! Since failure to control intra-abdominal disease remains the primary problem, there is considerable interest in the use of radiolabeled antibodies administered intra-peritoneal (IP). Several studies (including ours) targeting IP the tumor-associated antigen TAG-72 in EOC have shown encouraging results. CC49, a second-generation murine (m) anti-TAG-72 antibody, has an affinity constant six times higher than the original anti-TAG-72 antibody B72.3 and has shown a 16-fold increase in tumor: blood ratio using human xenografts in athymic mice compared with B72.3. The immunogenicity of mCC49, the long half-life (50h) and the projected even longer half-life of a chimeric or CDR-grafted version led to studies directed at humanization with deletion of various parts in search of a construct with low immunogenicity and half-life in the range of 15-40h. Humanized CC49 with a deleted CH2 region (HuCC49ACH2) fulfilled the criteria. Pre-clinical studies with HuCC49ACH2 showed that the plasma clearance is faster than the HuCC49 and the tumor to normal tissues ratio was higher compared with the HuCC49. Thus, HuCC49ACn2 was expected to have reduced immunogenicity (humanized version), to retain the dimeric binding site of the intact antibody, and to have relatively short circulation time in humans. Our pilot/phase I study of IV 131I-HuCC49ACH2 in patients with metastatic colorectal cancer showed a plasma T1/2 of 20 +/- 3h compared favorably with our prior data with mCC49 which had a T1/2 of 50 +/- 1h. All patients had positive radioimmune-imaging of at least one known tumor sites and there was low immunogenicity. Thus, in patients with relapsed or primary refractory EOC confined to the peritoneal cavity (+/- retroperitoneal nodes), we will: determine the maximum tolerated dose of IP l31I-HuCC49ACH2 and its toxicity profile; determine the plasma pharmacokinetics, whole body biodistribution, dosimetry and conjugate stability of HuCC49ACH2 administered IP; characterize the human immune response against 131I-HuCC49ACn2 given IP; and as a secondary endpoint, we will monitor for anti-tumor effects. The follow-up trial will be a phase II study to determine the efficacy of 131I-HuCC49ACH2 in resistant/refractory EOC patients.