Activation of complement pathways by univalent antibody derivatives with intact Fc zones

Watts, H. F.; Anderson, V A; Cole, V.M.; Stevenson, G T

doi:10.1016/0161-5890(85)90146-4

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…Polyclonal antibodies appear to be less sensitive than monoclonal antibodies to such constraints (24, 28, 29), potentially because binding of antibodies to a variety of antigens or epitopes facilitates clustering of Fc segments, thereby allowing efficient Fc-Fc assembly. Monovalent binding of IgG molecules in the platform is consistent with earlier observations (30) and could be envisaged to provide more degrees of freedom for the Fc segments, allowing their optimal positioning for C1q recruitment.…”

supporting

confidence: 85%

Complement Is Activated by IgG Hexamers Assembled at the Cell Surface

Diebolder

Beurskens

Jong

et al. 2014

Science

639

869

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Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. 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. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG isotypes. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.

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supporting

confidence: 85%

Complement Is Activated by IgG Hexamers Assembled at the Cell Surface

Diebolder

Beurskens

Jong

et al. 2014

Science

639

869

View full text Add to dashboard Cite

show abstract

“…Papain (25). Both papain and pepsin were used in preliminary studies, and both produced the same results.…”

Section: Methodsmentioning

confidence: 99%

Immunodominant antigen of Actinobacillus actinomycetemcomitans Y4 in high-responder patients

1989

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This study was undertaken to look for characteristics of the immunodominant antigen(s) of Actinobacillus actinomycetemcomitans Y4 that might help explain the high antibody titers in periodontitis patients. Radioimmunoassays (RIA) were performed on sera from 481 patients; sera from the 32 patients with the highest anti-Y4 titers (above 128,000 RIA U/mI) were further analyzed. Y4 antigen was boiled for 45 min or treated with papain, and antibody responses were analyzed by RIA and Western blotting (immunoblotting). In addition, carbohydrate was purified from Y4 and examined by Western blotting. The results indicated that the immunodominant antigen of Y4 in high responders was stable after papain treatment or boiling for 45 min. Papain or boiling eliminated protein bands but a large diffuse band persisted on Western blots. With increasing dilutions of sera, bands on Western blots corresponding to protein antigens disappeared, while the large diffuse band resembling that of carbohydrate persisted. Partially purified Y4 carbohydrate contained the large diffuse band. Double4mmunodiffusion analysis indicated that rabbit serotype b-specific antiserum and patient sera recognized the same antigen. When the carbohydrate extract was passed over a lipid A-binding column to remove lipopolysaccharide, the smear corresponding to the immunodominant antigen was still present on Western blots. The immunodominant antigen of Y4 in high-responder individuals appears to be a carbohydrate and is possibly the capsular polysaccharide.

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“…Here we show that bispecific IgG4 induces less C3b deposition than monospecific IgG4, which is particularly relevant for interpreting other studies on IgG4 complement activation that use monospecific antibody preparations. Interestingly, it has been previously shown that a monovalent IgG1 antibody outperformed its bivalent monospecific counterpart in CDC experiments ( 18 , 74 ). However, for another IgG1 antibody tested, both the monospecific and bispecific antibodies performed similarly ( 18 ), suggesting the effect may also be dependent on specific antigen-antibody interactions, like we have seen in our studies.…”

Section: Discussionmentioning

confidence: 98%

Factors affecting IgG4-mediated complement activation

et al. 2023

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Of the four human immunoglobulin G (IgG) subclasses, IgG4 is considered the least inflammatory, in part because it poorly activates the complement system. Regardless, in IgG4 related disease (IgG4-RD) and in autoimmune disorders with high levels of IgG4 autoantibodies, the presence of these antibodies has been linked to consumption and deposition of complement components. This apparent paradox suggests that conditions may exist, potentially reminiscent of in vivo deposits, that allow for complement activation by IgG4. Furthermore, it is currently unclear how variable glycosylation and Fab arm exchange may influence the ability of IgG4 to activate complement. Here, we used well-defined, glyco-engineered monoclonal preparations of IgG4 and determined their ability to activate complement in a controlled system. We show that IgG4 can activate complement only at high antigen and antibody concentrations, via the classical pathway. Moreover, elevated or reduced Fc galactosylation enhanced or diminished complement activation, respectively, with no apparent contribution from the lectin pathway. Fab glycans slightly reduced complement activation. Lastly, we show that bispecific, monovalent IgG4 resulting from Fab arm exchange is a less potent activator of complement than monospecific IgG4. Taken together, these results imply that involvement of IgG4-mediated complement activation in pathology is possible but unlikely.

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Activation of complement pathways by univalent antibody derivatives with intact Fc zones

Cited by 6 publications

References 30 publications

Complement Is Activated by IgG Hexamers Assembled at the Cell Surface

Complement Is Activated by IgG Hexamers Assembled at the Cell Surface

Immunodominant antigen of Actinobacillus actinomycetemcomitans Y4 in high-responder patients

Factors affecting IgG4-mediated complement activation

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