Radioimmunotherapy: An Anti-Neoplastic Strategy

描述(申请人提供)：尽管卵巢上皮性癌(EOC)手术后对一线化疗有很高的应答率，但5年DFS率很少超过15%。超过50%的经开腹手术确认完全缓解的患者将复发。显然，需要更有效的治疗！由于未能控制腹内疾病仍然是主要问题，因此对腹膜内注射放射性标记抗体(IP)的使用有相当大的兴趣。几项研究(包括我们的研究)针对卵巢癌中肿瘤相关抗原TAG-72的IP已显示出令人鼓舞的结果。CC49是第二代鼠(M)抗TAG-72抗体，其亲和力常数比最初的抗TAG-72抗体B72.3高6倍，并显示出与B72.3相比，在无瘤小鼠中使用人异种移植瘤与血的比率增加了16倍。MCC49的免疫原性、较长的半衰期(50h)以及嵌合体或CDR嫁接的半衰期甚至更长的半衰期导致了针对人源化的研究，通过删除不同部分来寻找免疫原性低且半衰期在15-40h范围内的构建体。CH2区缺失的人源化CC49(HuCC49ACH2)符合标准。临床前研究表明，与HuCC49相比，HuCC49ACH2的血浆清除速度更快，肿瘤与正常组织的比例更高。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部位，并在人体内具有相对较短的循环时间。我们在转移性结直肠癌患者中进行的IV 131I-HuCC49ACH2的试点/I期研究显示，与我们之前使用mCC49的t1/2为50+/-1h的数据相比，血浆t1/2为20+/-3h。所有患者至少有一个已知肿瘤部位的放射免疫成像阳性，且免疫原性低。因此，对于局限于腹膜后结节(+/-)的复发或原发难治性卵巢癌患者，我们将：确定IP 131I-HuCC49ACH2的最大耐受量及其毒性；确定IP给药的血浆药代动力学、全身生物分布、剂量学和结合稳定性；表征给定IP的人体对131I-HuCC49ACn2的免疫应答；以及作为次要终点，我们将监测抗肿瘤效果。后续试验将是第二阶段研究，以确定131I-HuCC49ACH2在难治性/难治性卵巢癌患者中的疗效。

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.