ACTIVATION OF COMPLEMENT BY AN IGG MOLECULE WITHOUT A GENETIC HINGE

THE hinge region links the two Fab arms to the Fc portion of the IgG m olecule. It mediates flexibility to the molecule and serves as a conne cting structure between the two heavy chains. In addition it provides space between the Fab and Fc parts. All three properties have been pro posed to be important for the ability of IgG to initiate complement ac tivation leading to complement-mediated cell lysis (CML)1. Here we rep ort the construction of a hinge-deleted mouse-human chimaeric IgG3 mol ecule with specificity for the hapten NIP (3-iodo-4-hydroxy-5-nitrophe nacetyl), HM-1. HM-1 lacks the genetic hinge, but has an introduced cy steine between Ala 231 (EU numbering) and Pro 232 in the lower hinge e ncoded by the C(H)2 exon. The introduced cysteine forms a disulphide b ond between the two heavy chains of the molecule. In CML, HM-1 shows a greater activity than IgG3 wild type. This is the first time an IgG m olecule without a genetic hinge has been found to be active in CML. We conclude that the hinge functioning as a spacer is not a prerequisite for complement activation. Rather, its major role seems to be to conn ect the heavy chains to each other in the amino-terminal part of C(H)2 . Because HM-1 is expected to have low Fab-Fc flexibility, this molecu lar feature is probably of no importance for complement activation.