BIFUNCTIONAL ANTIBODY MEDIATED NEUTRON CAPTURE THERAPY

一个跨学科的努力，在化学，生物学的前沿， 免疫学的提出将拓宽有关研究的范围 随着硼-10中子俘获反应的应用， 10 B（n，alpha）7 Li，用于癌症治疗（BNCT）。 这里采取的方法 涉及含10 B的试剂与肿瘤的半抗原亲和结合 使用双功能免疫蛋白， 10B（C）10-30 μ g 10 B/g肿瘤）可被递送至肿瘤细胞表面 抗原 大约103个10 B原子必须与每个原子结合， 双功能免疫反应性物种和使用几乎所有的特异性 需要靶向抗原位点。 本研究中使用的含10 B的试剂将是 低聚物（20聚体种类），每个含有约200个10 B原子，并富含 半抗原组。 这些肽样低聚物是使用 碳硼烷衍生的α-氨基酸和梅里菲尔德方法。 类似的 可获得一系列精确构建的富硼聚酰胺低聚物 由二羧酸和二胺制备。 所有 由于存在适当的取代基，低聚物是亲水性的。 20聚体种类使得它们可以被放射性标记或荧光标记 在与合成的多歧管接头（MF）直接缀合之前， 结合一定数量（5或10）的20聚体种类。 双官能 将合成能够结合肿瘤细胞的抗体 抗原和MF-（20聚体）n物质，从而避免化学 硼载体和肿瘤导向免疫球蛋白之间的键。 一个新 需要识别20聚体一部分杂交瘤。 人与生物圈 来自该杂交瘤的杂交瘤细胞将被切割成Fab ′并化学连接 与来源于抗CEA Mab T84.12的F（ab '）2。 第二个双功能 抗体将利用高亲和力的链霉亲和素-生物素结合 互动 在该系统中，T84.12 F（ab '）2将与 链霉亲和素，20聚体和MF-（20聚体）n物质将与 生物素。

An interdisciplinary effort at the frontiers of chemistry, biology, and immunology is proposed which will broaden the scope of research concerned with the application of the boron-10 neutron capture reaction, 10B(n,alpha)7Li, to cancer therapy (BNCT). The approach taken here involves the hapten-affinity binding of 10B-containing reagents to tumor using bifunctional immunoproteins in such a manner that therapeutic amounts of 10B (ca. 10-30 mug 10B/g tumor) can be delivered to tumor cell surface antigens. Approximately 103 10B atoms must be combined with each bifunctional immunoreactive species and the use of nearly all specifically targeted antigenic sites is required. The 10B-containing reagents to be employed in this research will be oligomers (20 mer species) containing about 200 10B-atoms each and rich in hapten groups. These peptide-like oligomers are synthesized using carborane derived alpha-amino acids and Merrifield procedures. A similar family of precisely constructed boron-rich polyamide oligomers is available from dicarboxylic acids and diamines using similar procedures. All oligomers are hydrophilic due to the presence of appropriate substituents. The 20 mer species are such that they may be radio- or fluorescence-labeled prior to direct conjugation with a synthetic manifold linker (MF) capable of binding a definite number (5 or 10) of 20 mer species. A bifunctional antibody will be synthesized which will be capable of binding tumor cell antigen and the MF-(20 mer)n species simultaneously, thus avoiding chemical bonds between the boron carrier and tumor-seeking immunoglobulin. A new hybridoma will be required which recognizes a portion of 20 mer. The Mab derived from this hybridoma will be cleaved to a Fab' and chemically linked to the F(ab')2 derived from anti-CEA Mab T84.12. A second bifunctional antibody will employ the high-affinity streptavidin-biotin binding interaction. In this system, T84.12 F(ab')2 will be chemically linked with streptavidin, and 20 mer and MF-(20 mer)n species will be conjugated with biotin.