Immunoglobulin G (IgG), all four human subclasses

Class

IgG-degrading endopeptidase (biologic enzyme derived from Streptococcus pyogenes IdeS)

Pathway

Antibody cleavage for transplant desensitization (cleaves both cell-bound and soluble IgG, including anti-HLA donor-specific antibodies, within hours)

This target is not a receptor or enzyme within human physiology but the human antibody class Immunoglobulin G (IgG) itself, which is degraded by a bacterial enzyme derived from Streptococcus pyogenes. IgG antibodies, produced by plasma cells, recognize and bind specific antigens; when directed against a transplanted organ's tissue antigens (human leukocyte antigens, or HLA), they can trigger antibody-mediated rejection by activating complement and engaging immune effector cells. The enzyme cleaves IgG molecules at a conserved site in the hinge region, splitting them into fragments that can no longer bind antigen effectively or engage the complement and Fc-receptor systems that drive tissue damage. Because the cleavage site is common to all four human IgG subclasses, the enzyme eliminates essentially the entire circulating and tissue-bound IgG pool within a short time, including antibodies directed against a prospective donor organ. This mechanism is used to reduce preexisting antibody levels rapidly enough to permit transplantation in individuals who would otherwise be excluded because their antibody repertoire would attack the graft. Beyond transplantation, the same principle of rapid antibody depletion is relevant conceptually to other IgG-driven autoimmune conditions, where antibody clearance could interrupt disease-causing immune reactions.