Toward antibody-catalyzed hydrolysis of organophosphorus poisons.
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.
Vayron
P
P
CEA, Service des Molécules Marquées, DBCM, and Service de Pharmacologie et d'Immunologie, DRM, CE Saclay 91191, Gif sur Yvette Cedex, France.
Renard
P Y
PY
Taran
F
F
Créminon
C
C
Frobert
Y
Y
Grassi
J
J
Mioskowski
C
C
D000818:Animals; D017151:Antibodies, Catalytic / Q000737:chemistry* / Q000276:immunology / Q000302:isolation & purification*; D000918:Antibody Specificity; D006241:Haptens; D006868:Hydrolysis; D051379:Mice; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011041:Poisoning / Q000276:immunology / Q000517:prevention & control; D011042:Poisons / Q000737:chemistry / Q000276:immunology
D017151:Antibodies, Catalytic; D006241:Haptens; D009943:Organophosphorus Compounds; D011042:Poisons