Vayron P, Renard P Y, Taran F, Créminon C, Frobert Y, Grassi J, Mioskowski C
CEA, Service des Molécules Marquées, DBCM, and Service de Pharmacologie et d'Immunologie, DRM, CE Saclay 91191, Gif sur Yvette Cedex, France.
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7058-63. doi: 10.1073/pnas.97.13.7058.
We report here our preliminary results on the use of catalytic antibodies as an approach to neutralizing organophosphorus chemical weapons. A first-generation hapten, methyl-alpha-hydroxyphosphinate Ha, was designed to mimic the approach of an incoming water molecule for the hydrolysis of exceedingly toxic methylphosphonothioate VX (1a). A moderate protective activity was first observed on polyclonal antibodies raised against Ha. The results were further confirmed by using a mAb PAR 15 raised against phenyl-alpha-hydroxyphosphinate Hb, which catalyzes the hydrolysis of PhX (1b), a less toxic phenylphosphonothioate analog of VX with a rate constant of 0.36 M(-1) x min(-1) at pH 7.4 and 25 degrees C, which corresponds to a catalytic proficiency of 14,400 M(-1) toward the rate constant for the uncatalyzed hydrolysis of 1b. This is a demonstration on the organophosphorus poisons themselves that mAbs can catalytically hydrolyze nerve agents, and a significant step toward the production of therapeutically active abzymes to treat poisoning by warfare agents.
我们在此报告关于使用催化抗体作为中和有机磷化学武器方法的初步结果。第一代半抗原甲基-α-羟基次膦酸酯Ha被设计用于模拟进入的水分子对剧毒甲基硫代膦酸酯VX（1a）进行水解的方式。首次在针对Ha产生的多克隆抗体上观察到了适度的保护活性。通过使用针对苯基-α-羟基次膦酸酯Hb产生的单克隆抗体PAR 15进一步证实了这些结果，该抗体催化苯基硫代膦酸酯PhX（1b）的水解，PhX是VX毒性较小的苯基硫代膦酸酯类似物，在pH 7.4和25℃下的速率常数为0.36 M⁻¹×min⁻¹，这对应于相对于1b未催化水解速率常数的14400 M⁻¹的催化效率。这证明了单克隆抗体可以催化水解神经毒剂本身，并且朝着生产用于治疗战剂中毒的具有治疗活性的抗体酶迈出了重要一步。
