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(申请人提供)：结直肠癌占所有癌症的15%，转移性肿瘤患者的5年生存率接近于零。靶向放射治疗或放射免疫治疗(RAIT)有可能在小体积结直肠癌疾病中产生持久的临床疗效。这项拟议工作的最终目标是利用人源化的抗CEA单抗(MAb)HMN-14和细胞内捕获的碘-131放射性核素I-131-IMPR4产生一种临床上有用的、商业上可行的放射免疫疗法，用于治疗结直肠癌的微小疾病。后者是一种特殊设计的放射性碘化肽，其结构特征有助于载体单抗分解代谢后的残留物，解决了与直接放射性碘化单抗相关的体内脱碘问题。第一阶段研究的近期目标是获得临床前证据，证明I-131-IMPR4标记的HMN-14(I-131-IMPR4-HMN-14)在肿瘤摄取和放射性保留方面明显优于直接放射性碘标记的HMN-14(I-131-HMN-14)。这将通过(I)比较四种结肠癌细胞系对两种标记的体外结合和处理，以及(Ii)通过在裸鼠结肠癌人肿瘤移植模型中的靶向和最大耐受量(MTD)/治疗实验来确定。同时的一个目标是提高I-131-IMPR4-HMN-14的可实现的比活度。成功的标准将是：(1)在体外实验中，I-131-IMPR4标记与直接I-131标记相比，肿瘤细胞对放射性的保留增加了50%-200%，(2)在临床前MTD/治疗研究中，残留I-131标记相对于直接I-131标记具有治疗优势的初步证据，以及(3)在使用I-131-IMPR4的放射性碘中，比活度提高到10mCI/mg。成功的可行性研究将导致延长的临床前治疗研究，并在SBIR第二阶段计划中启动临床第一阶段RAIT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