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较高，但5年DFS率很少超过15%。超过50%的剖腹手术证实完全缓解的患者会复发。显然，需要更有效的治疗！由于未能控制腹腔内疾病仍然是主要问题，因此对使用腹膜内（IP）给药的放射性标记抗体有相当大的兴趣。几项研究（包括我们的）靶向IP肿瘤相关抗原TAG-72在EOC中显示了令人鼓舞的结果。CC 49是第二代鼠（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，并且与B72.3相比，在无胸腺小鼠中使用人异种移植物时，其肿瘤：血液比增加了16倍。mCC 49的免疫原性、长半衰期（50小时）和嵌合或CDR移植形式的预计甚至更长的半衰期导致针对通过缺失各个部分的人源化的研究，以寻找具有低免疫原性和在15- 40小时范围内的半衰期的构建体。CH 2区缺失的人源化CC 49（HuCC 49 ACH 2）符合标准。HuCC 49 ACH 2的临床前研究表明，血浆清除速度比HuCC 49更快，肿瘤与正常组织的比例比HuCC 49更高。因此，预期HuCC 49 ACn 2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，并且在人体内具有相对短的循环时间。我们在转移性结直肠癌患者中进行的IV 131 I-HuCC 49 ACH 2的初步/I期研究显示，血浆T1/2为20 +/-3 h，优于我们先前使用mCC 49的数据，后者的T1/2为50 +/-1 h。所有患者至少有一个已知肿瘤部位的放射免疫显像阳性，免疫原性低。因此，在局限于腹膜腔的复发性或原发性难治性EOC患者中，确定IP 131 I-HuCC 49 ACH 2的最大耐受剂量及其毒性特征;确定IP施用的HuCC 49 ACH 2的血浆药代动力学、全身生物分布、剂量测定和缀合物稳定性;表征针对IP施用的131 I-HuCC 49 ACH 2的人免疫应答;作为次要终点，我们将监测抗肿瘤作用。后续试验将是一项II期研究，以确定131 I-HuCC 49 ACH 2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.