Minimal-disease radioimmunotherapy of colorectal cancer

结直肠癌微病放射免疫治疗

• 批准号: 6690175
• 负责人: SERENGULAM V GOVINDAN
• 金额: $ 10万
• 依托单位: IMMUNOMEDICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690175
• 关键词: athymic mouse; carcinoembryonal antigen; cell line; colorectal neoplasms; drug design /synthesis /production; drug screening /evaluation; immunologic substance development /preparation; minimal residual disease; monoclonal antibody; neoplasm /cancer radioimmunotherapy; pharmacokinetics

DESCRIPTION (provided by applicant): Colorectal cancer accounts for 15% of all cancers, and the 5-year survival rate for patients with metastatic tumors is close to zero. Targeted radiotherapy or radioimmunotherapy (RAIT) has the potential to bring about durable clinical responses in small-volume disease of colorectal cancer. The ultimate goal of the proposed work is to produce a clinically useful, commercially viable, radioimmunotherapeutic for treating minimal-disease of colorectal cancer using a humanized anti-CEA monoclonal antibody (MAb), hMN-14, and an intracellularly trapped form ('residualizing') of iodine-131 radionuclide, I-131-IMPR4. The latter is a specially designed radioiodinated peptide, with structural features to aid in residualization after catabolism of the carrier MAb, which solves the problem of in vivo 'deiodination' associated with directly radioiodinated MAbs. The immediate goal of the Phase I research is to obtain preclinical proof that hMN-14 labeled with I-131-IMPR4 (I-131-IMPR4-hMN-14) is significantly better than directly radioiodinated hMN-14 (I-131-hMN-14) in terms of tumor uptake and retention of radioactivity. This will be determined by (i) comparing in vitro bindings and processing of the two labels by four colorectal cell lines, and (ii) by targeting and maximum-tolerated-dose (MTD)/therapy experiments in a human tumor xenograft model of colon carcinoma in nude mice. A concurrent objective is to improve the achievable specific activity of I-131-IMPR4-hMN-14. Criteria of success will be the findings of (1) a 50-200% increase in tumor-cell retention of radioactivity of I-131-IMPR4 label versus direct I-131 label in in vitro experiments, (2) a preliminary evidence of therapeutic advantage for the residualizing I-131 versus direct I-131 label in the preclinical MTD/therapy study, and (3) specific activity enhancement to 10 mCi/mg in radioiodinations with I-131-IMPR4. Successful feasibility study will lead to extended preclinical therapy studies and the initiation of a clinical Phase I RAIT trial in a SBIR Phase II program.

描述（由申请人提供）：大肠癌占所有癌症的15％，转移性肿瘤患者的5年存活率接近零。靶向放射疗法或放射免疫疗法（RAIT）有可能在大批量的结直肠癌疾病中产生持久的临床反应。拟议工作的最终目的是生产一种有用的，商业上可行的放射免疫疗法，用于使用人源化的抗CEA单克隆抗体（MAB），HMN-14和细胞内诱捕的形式（'残留）（''' iodine-131 radionuclide，i-131-impr4。后者是一种特殊设计的放射性约束肽，具有结构性特征，可帮助载体mAB分解代谢后残留，这解决了与直接放射性二世mab相关的体内“去二化”的问题。 I阶段研究的直接目标是获得临床前证明，表明用I-131-IMPR4（I-131-IMPR4-HMN-14）标记的HMN-14要比直接放射性验证的HMN-14（I-131-HMN）要好得多。 -14）就肿瘤吸收和放射性保留而言。这将通过（i）通过（i）通过四个结直肠细胞系比较两个标签的体外结合和处理，以及（ii）通过人类肿瘤异种移植模型的靶向和最大耐受剂量（MTD）/治疗实验裸鼠癌。并发目标是改善I-131-IMPR4-HMN-14的可实现的特定活性。成功的标准将是（1）在体外实验中与直接I-131标签的I-131-IMPR4标签的肿瘤细胞保留性增加50-200％的发现，（2）在临床前MTD/治疗研究中，I-131与直接I-131标签的差异优势，以及（3）I-131-IMPR4的放射性置换中10 MCI/mg的特定活性增强。成功的可行性研究将导致扩展的临床前治疗研究，并在SBIR II期计划中开始进行I阶段I阶段试验。

项目成果

Clinical-scale radiolabeling of a humanized anticarcinoembryonic antigen monoclonal antibody, hMN-14, with residualizing 131I for use in radioimmunotherapy.

• 发表时间: 2005
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: S. Govindan;G. Griffiths;R. Stein;Philip M. Andrews;R. Sharkey;H. Hansen;I. Horak;D. Goldenberg

Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibody.

残留碘放射性标记在抗癌胚抗原单克隆抗体靶向结肠癌异种移植物治疗中的优势。

• DOI: 10.1158/1078-0432.ccr-04-2100
• 发表时间: 2005
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Stein,Rhona;Govindan,SerengulamV;Hayes,Marianne;Griffiths,GaryL;Hansen,HansJ;Horak,IvanD;Goldenberg,DavidM
• 通讯作者: Goldenberg,DavidM