USE OF VASOACTIVE PEPTIDES TO MODIFY MONOCLONAL ANTIBODY PHARMACOLOGY

与肿瘤相关抗原反应的单抗正在研制中 研究它们对癌症治疗的效用，或者单独作为一种 细胞毒性的免疫介体，或与药物、毒素或 放射性核素。放射性标记单抗的一个重要问题是它们的 相对不能接触到肿瘤所有区域的足够数量。 由于单抗结合物的大尺寸，内皮细胞和 网状内皮组织作为限制出口的限制性屏障 从这些大分子的血管内空间。因为这个原因， 暂时增加血管通透性的能力正在接受 高度重视作为提高肿瘤摄取高度放射性物质的一种方法 血液中的特定单抗。 参与这项研究的调查人员已经开发出一种 构象受限的稳定十肽激动剂小组 与人类C5a的C-末端“效应器”区域相对应 具有增加血管通透性的能力。这个项目将 C5a十肽与单抗B72.3偶联方法的研究 而不会失去激动肽的血管活性 单抗的特异性/亲和力。此外，在体内使用的 将研究MAb-C5a多肽结构以确定最佳 十肽和连接物联合应用改善肿瘤的分布 放射性标记的单抗。这些研究将导致临床的准备工作。 为今后的临床放射免疫治疗研究提供分级材料。

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.