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Activation of complement by an IgG molecule without a genetic hinge

O H Brekke¹, T E Michaelsen, R Sandin

¹Department of Biology, University of Oslo, Blindern, Norway.

|June 17, 1993

Summary

Researchers created a modified IgG3 antibody, HM-1, lacking a genetic hinge but retaining complement-mediated cell lysis (CML) activity. This suggests the IgG hinge

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Area of Science:

Immunology
Molecular Biology
Biochemistry

Background:

The hinge region of immunoglobulin G (IgG) is crucial for molecular flexibility and connecting heavy chains, proposed to be vital for complement activation.
Complement-mediated cell lysis (CML) is a key immune response mediated by IgG antibodies.

Purpose of the Study:

To investigate the role of the IgG hinge region in complement activation and CML.
To construct and characterize a novel hinge-deleted IgG3 molecule.

Main Methods:

Construction of a hinge-deleted mouse-human chimeric IgG3 molecule (HM-1) with specificity for NIP.
Introduction of a cysteine residue to form a disulfide bond between heavy chains in the absence of a genetic hinge.
Assessment of HM-1 activity in complement-mediated cell lysis (CML) assays.

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Main Results:

The engineered HM-1 molecule, lacking a genetic hinge but possessing an introduced disulfide bond, demonstrated enhanced activity in CML compared to wild-type IgG3.
This is the first report of a hinge-less IgG molecule exhibiting CML activity.
HM-1 is expected to have reduced Fab-Fc flexibility.

Conclusions:

The IgG hinge's function as a spacer is not essential for complement activation.
The primary role of the hinge may be to connect heavy chains in the CH2 domain.
Fab-Fc flexibility is likely not a prerequisite for IgG-mediated complement activation.