BISPECIFIC ANTIBODIES OVERCOME THE OPSONIN-RECEPTOR MISMATCH OF CYSTIC-FIBROSIS IN-VITRO - RESTORATION OF NEUTROPHIL-MEDIATED PHAGOCYTOSIS AND KILLING OF PSEUDOMONAS-AERUGINOSA

Inflammation and infection associated with bacterial pathogens, primar ily Pseudomonas aeruginosa (Pa), are the primary causes of morbidity a nd mortality for cystic fibrosis (CF) patients. CF patients may be pre disposed to these bacterial infections by a defect in phagocytosis due to ''opsonin-receptor mismatch,'' in which a complement receptor (CR1 ) and an important opsonin (iC3b) are destroyed by proteolytic enzymes , We show that opsonin-receptor mismatch can be mitigated in vitro usi ng a bispecific Ab (bsAb) to cross-link neutrophils via the beta-chain of leukocyte integrins (CD18) to bacterial epitopes or C3d on opsoniz ed Pa. Two chemically cross-linked bsAb were constructed with mAb spec ific for C3d (or the O-specific side chain of Fisher Devlin Immunotype 1 Pa) and CD18. Using an in vitro model of elastase-mediated opsonin- receptor mismatch, these bsAb specifically enhanced Pa phagocytosis an d killing, with the anti-C3d-containing bsAb restoring the levels of p hagocytosis to approximately those for the non-elastase-treated opsoni c control. These results encourage the further investigation of bsAb a s therapeutic agents for bacterial infection in the lungs of CF patien ts.