Immunoglobulin G lower hinge region (IgG lower hinge)

The Immunoglobulin G (IgG) lower hinge region is a flexible amino acid sequence connecting the upper hinge to the CH2 domain of the antibody heavy chain (Sondermann et al., 2000, PMID: 10910368). It plays a pivotal role in the immune system by serving as the primary binding site for Fc-gamma receptors (FcγRs) found on various immune cells, such as natural killer cells and macrophages. Additionally, this region is essential for the binding of C1q, the initiating protein of the classical complement pathway, thereby facilitating complement-dependent cytotoxicity (CDC). Because it mediates critical effector functions like antibody-dependent cellular cytotoxicity (ADCC), it is a major focal point for therapeutic intervention and protein engineering. The drug imlifidase (IdeS) specifically targets and cleaves this region to rapidly neutralize pathogenic IgG antibodies in conditions like Goodpasture syndrome and organ transplant rejection (Jordan et al., 2017, PMID: 28763530). In drug development, the lower hinge is frequently modified via site-directed mutagenesis, such as the LALA (Leu234Ala, Leu235Ala) mutation, to silence effector functions in monoclonal antibodies intended for simple neutralization (Strohl, 2009, PMID: 19879739). This structural domain is thus critical for both the natural immune response and the design of next-generation biopharmaceuticals.

Other names

IgG hinge regionCH2 domain N-terminal regionFc gamma receptor binding siteLower hinge domainIgG CH2-hinge interface

Imlifidase acts as a highly specific cysteine protease that cleaves the IgG heavy chain at the lower hinge region, specifically between Gly236 and Gly237, which separates the Fab fragments from the Fc region and abolishes Fc-mediated effector functions.