title: Bispecific antibodies overcome the opsonin-receptor mismatch of cystic fibrosis in vitro: restoration of neutrophil-mediated phagocytosis and killing of Pseudomonas aeruginosa.
abstract: Inflammation and infection associated with bacterial pathogens, primarily Pseudomonas aeruginosa (Pa), are the primary causes of morbidity and mortality for cystic fibrosis (CF) patients. CF patients may be predisposed 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 using a bispecific Ab (bsAb) to cross-link neutrophils via the beta-chain of leukocyte integrins (CD18) to bacterial epitopes or C3d on opsonized Pa. Two chemically cross-linked bsAb were constructed with mAb specific 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 and killing, with the anti-C3d-containing bsAb restoring the levels of phagocytosis to approximately those for the non-elastase-treated opsonic control. These results encourage the further investigation of bsAb as therapeutic agents for bacterial infection in the lungs of CF patients.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: McCormick
authors.forename: A Y
authors.initials: AY
authors.lastname: Karulin
authors.forename: J R
authors.initials: JR
authors.lastname: Schreiber
authors.forename: N S
authors.initials: NS
authors.lastname: Greenspan
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D000918:Antibody Specificity; D018821:CD18 Antigens / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology; D003550:Cystic Fibrosis / Q000276:immunology* / Q000382:microbiology*; D005434:Flow Cytometry; D006801:Humans; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009895:Opsonin Proteins / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011552:Pseudomonas Infections / Q000276:immunology*; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D018033:Antibodies, Bispecific; D018821:CD18 Antigens; D009895:Opsonin Proteins; D011971:Receptors, Immunologic; C091196:opsonin receptor; D003165:Complement System Proteins