USE OF VASOACTIVE PEPTIDES TO MODIFY MONOCLONAL ANTIBODY PHARMACOLOGY

与肿瘤相关抗原反应的单克隆抗体正在被 研究了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 放射性核素。 放射性标记的单克隆抗体的一个重要问题是它们的 足够数量的相对不可接近肿瘤的所有区域。 由于MAb-缀合物的大尺寸，内皮和 网状内皮组织作为限制性屏障限制了出口 这些大分子的血管内空间。 基于这个理由， 暂时增加血管渗透性能力正在接受 作为一种增强肿瘤对高浓度的 血液中的特异性抗体 参与这项研究的研究人员已经开发了一种 一组稳定的构象受限的十肽激动剂 对应于人C5 a的C-末端“效应”区， 有能力增加血管通透性。 该项目将 研究C5 a十肽与MAb B72.3的偶联方法 而不损失激动剂肽或 MAb的特异性/亲合力。 此外，在体内使用的， 将研究Mab-C5 a肽构建体，以确定最佳的Mab-C5 a肽构建体。 十肽和接头组合以改善肿瘤分布 放射性标记的单克隆抗体。 这些研究将导致临床准备 为将来的临床放射免疫治疗研究提供材料。

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.