Human monoclonal antibody homodimers. Effect of valency on in vitro and in vivo antibacterial activity.
Human IgG1 mAb dimers specific for either group B streptococci or Escherichia coli K1 bacteria were formed using chemical cross-linkers. The effect of antibody valency on biologic efficacy was investigated by comparing the IgG dimers against the corresponding IgG monomers. Binding activity and relative avidity were assessed using Ag binding and competition ELISA, and functional activity was analyzed using opsonophagocytic assays. These in vitro assays revealed that the dimers were greater than or equal to 50-fold more active than the monomers. A neonatal rat infection model showed the in vivo protective efficacy of the dimers was greater than or equal to 20-fold greater than that of the monomers. Enhancing the activity of mAb by chemical cross-linking may be a useful strategy for salvaging low affinity IgG mAb that possess poor functional properties.
Wolff
E A
EA
Molecular Sciences Department, Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA 98121.
Esselstyn
J
J
Maloney
G
G
Raff
H V
HV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D004927:Escherichia coli Infections / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D010587:Phagocytosis; D051381:Rats; D011919:Rats, Inbred Strains
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G