On-target IgG hexamerisation driven by a C-terminal IgM tail …
2021年9月2日 · Ablating covalent hexamerisation with the C575S mutation reduced the potency of CDC activation but also obviated the negative impacts associated with covalent IgG hexamers; notably purification...
Stellabody: A novel hexamer‐promoting mutation for improved IgG …
2024年10月4日 · Combining hexamer-enhancing mutations has been shown to increase the propensity of IgG molecules to form hexamers in solution, as double mutants (e.g., E345R/E430G) produce a population of 7%–13% preformed hexamer and triple mutants (e.g., E345R/E430G/S440Y) produce a population of 50%–80% preformed hexamer. 49, 50 The …
Complement Is Activated by IgG Hexamers Assembled at the Cell …
2014年3月14日 · We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade.
Biophysical Characterization and Stability of Modified IgG1 …
2022年6月1日 · In this work, we assessed the colloidal, conformational, and long-term stability of IgG model compounds with stepwise increasing hexamer formation propensity. The chosen IgG model compounds were based on the HexaBody technology for which self-association was driven by the stabilization of interactions at a well-characterized Fc-Fc interface 35 ...
A Novel Platform for the Potentiation of Therapeutic Antibodies …
2016年1月6日 · We recently showed that IgG antibodies organize into ordered hexamers on cell surfaces following antigen binding. These IgG hexamers bind and activate C1, the first component in the classical complement pathway that leads to target cell killing by complement-dependent cytotoxicity (CDC) via membrane attack complexes (MACs) that breach the cell ...
Fc Galactosylation Promotes Hexamerization of Human IgG1, …
2021年9月9日 · CDC can be initiated upon binding of many molecules of IgG to a multivalent Ag, which allows multimerization of neighboring IgG–Fc tails. The prototypic structure is a hexamer, which forms an optimal platform for C1q binding (15, 16). This leads to activation of the C1r and C1s complex, starting the complement cascade by depositing C4b and ...
AN IMMUNOLOGIC HEX: Novel Insights Into Mechanisms of …
2015年5月1日 · Disruption of IgG hexamers may stymie the ability of alloantibodies to elicit complement activation and local inflammation within the allograft. Second, the observation that IgG hexamerization following antigen binding results in more efficient complement activation might be exploited therapeutically by artificially increasing Fc-Fc contact ...
Hexamerization: explaining the original sin of IgG-mediated …
2024年6月4日 · In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation.
Structure of IgG-Fc hexamer reveals a mutual lock-and-key mode …
2022年2月25日 · This study shows that hexamer assembly is an important event determining the ability of IgG to trigger acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.
On-target IgG hexamerisation driven by a C-terminal IgM tail …
2021年9月2日 · Herein is described an approach to exploit the tailpiece of the naturally multimeric IgM to augment hexamerisation of IgG. Fusion of the C-terminal tailpiece of IgM promoted spontaneous hIgG hexamer formation, resulting in enhanced C1q recruitment and complement-dependent cytotoxicity (CDC) but with off-target complement activation and reduced ...