USE OF VASOACTIVE PEPTIDES TO MODIFY MONOCLONAL ANTIBODY PHARMACOLOGY

使用血管活性肽来改变单克隆抗体药理学

• 批准号: 6103307
• 负责人: DAVID MORRIS COLCHER
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-25 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103307
• 关键词: adenocarcinoma; antitumor antibody; athymic mouse; colorectal neoplasms; complement; drug design /synthesis /production; hamsters; human tissue; immunoconjugates; indium; iodine; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; pancreas neoplasms; pharmacokinetics; radionuclides; yttrium

Monoclonal antibodies reactive with tumor associated antigens are being studied for their utility for cancer therapy, either alone as an immunologic mediator of cytotoxicity, or conjugated to a drug, toxin, or radionuclide. A significant problem with radiolabeled MAbs is their relative inaccessibility to all regions of a tumor in adequate quantities. Because of the large size of the MAb-conjugates, endothelial and reticuloendothelial tissues act as restrictive barriers limiting the egress from the intravascular space of these large molecules. For this reason, the ability to transiently increase vascular permeability is receiving considerable attention as a way of enhancing tumor uptake of highly specific MAbs from the blood. The investigators involved in this research initiative have developed a panel of stable conformationally constrained decapeptide agonists corresponding to the C-terminal "effector" region of human C5a that have the ability to increase vascular permeability. This project will investigate methods of conjugation of the C5a decapeptides to MAb B72.3 without loss of the vasoactivity of the agonist peptides or the specificity/ avidity of the MAb. Furthermore, the in vivo use of the Mab-C5a peptide constructs will be studied to determine the optimal decapeptide and linker combination to improve the tumor distribution of radiolabeled MAbs. These studies will lead to the preparation of clinical grade materials for future clinical radioimmunotherapy studies.

与肿瘤相关抗原发生反应的单克隆抗体正在被 研究它们在癌症治疗中的效用，无论是单独作为一种 细胞毒性的免疫介质，或与药物、毒素或药物缀合 放射性核素。 放射性标记单克隆抗体的一个重要问题是它们 相对难以以足够的量到达肿瘤的所有区域。 由于 MAb 缀合物尺寸较大，内皮细胞和 网状内皮组织充当限制性屏障，限制出口 来自这些大分子的血管内空间。 为此原因， 暂时增加血管通透性的能力正在接受 作为一种增强肿瘤摄取高度 来自血液的特定单克隆抗体。 参与这项研究计划的研究人员开发了一种 稳定构象限制的十肽激动剂组 对应于人类 C5a 的 C 末端“效应器”区域 具有增加血管通透性的能力。 该项目将 研究 C5a 十肽与 MAb B72.3 的缀合方法 不丧失激动剂肽或血管活性 MAb 的特异性/亲合力。 此外，体内使用 将研究 Mab-C5a 肽构建体以确定最佳 十肽和接头组合改善肿瘤分布 放射性标记的单克隆抗体。 这些研究将导致临床准备 未来临床放射免疫治疗研究的等级材料。