An IgG3 switch variant of rituximab mediates enhanced complement‐dependent cytotoxicity against tumour cells with low <scp>CD</scp>20 expression levels

Rösner, Thies; Derer, Stefanie; Kellner, Christian; Dechant, Michael; Lohse, Stefan; Vidarsson, Gestur; Peipp, Matthias; Valerius, Thomas

doi:10.1111/bjh.12209

Cited by 23 publications

(21 citation statements)

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“…In line with these findings, a previous study reported superior human IgG3-induced CML of tumor cells expressing high CD55 and CD59 but low CD46 levels by neutralization of CD46, CD55, and CD59 compared with sole neutralization of CD59 on these cells (36). Moreover, recent data revealed human IgG3 specific for CD20 to more potently trigger CML of CD55-expressing CLL cells than the human IgG1 counterpart, potentially pointing to different mechanisms of action of human IgG3 Abs displaying distinct target Ag specificities (18). CD55, the decay-accelerating factor of C3 (C4b2b/C4b2a or C3bBb) and C5 (C4b2b3b/C4b2a3b or C3bBb3b) convertases, is a GPI-anchored protein that is widely expressed in human cells.…”

Section: Discussionmentioning

confidence: 79%

“…This difference in CDC activity has been ascribed to the 4-fold longer hinge region, as well as to the higher flexibility of human IgG3 compared with human IgG1, enabling IgG3 to better span widely spaced Ag molecules (13,16,17). Referring to these structural features, an IgG3 isotype switch variant of the therapeutic IgG1 Ab rituximab has been demonstrated to possess superior complement-activating capacity against CD20 low-expressing cells such as chronic lymphocytic leukemia cells (18). However, contrasting results also have been reported regarding complement activation by human IgG1 and IgG3, demonstrating lower complement-activating capacities for IgG3 than for IgG1 (12).…”

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confidence: 99%

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Epidermal Growth Factor Receptor Targeting IgG3 Triggers Complement-Mediated Lysis of Decay-Accelerating Factor Expressing Tumor Cells through the Alternative Pathway Amplification Loop

Rösner

Lohse

Peipp

et al. 2014

The Journal of Immunology

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Binding of C1q to target-bound IgG initiates complement-mediated lysis (CML) of pathogens, as well as of malignant or apoptotic cells, and thus constitutes an integral part of the innate immune system. Despite its prominent molecular flexibility and higher C1q binding affinity compared with human IgG1, IgG3 does not consistently promote superior CML. Hence the aim of this study was to investigate underlying molecular mechanisms of IgG1- and IgG3-driven complement activation using isotype variants of the therapeutic epidermal growth factor receptor (EGFR) Ab cetuximab. Both IgG1 and IgG3 Abs demonstrated similar EGFR binding and similar efficiency in Fab-mediated effector mechanisms. Whereas anti–EGFR-IgG1 did not promote CML of investigated target cells, anti–EGFR-IgG3 triggered significant CML of some, but not all tested cell lines. CML triggered by anti–EGFR-IgG3 negatively correlated with expression levels of the membrane-bound complement regulatory proteins CD55 and CD59, but not CD46. Notably, anti–EGFR-IgG3 promoted strong C1q and C3b, but relatively low C4b and C5b-9 deposition on analyzed cell lines. Furthermore, anti–EGFR-IgG3 triggered C4a release on all cells but failed to induce C3a and C5a release on CD55/CD59 highly expressing cells. RNA interference-induced knockdown or overexpression of membrane-bound complement regulatory proteins revealed CD55 expression to be a pivotal determinant of anti–EGFR-IgG3–triggered CML and to force a switch from classical complement pathway activation to C1q-dependent alternative pathway amplification. Together, these data suggest human anti–EGFR-IgG3, although highly reactive with C1q, to weakly promote assembly of the classical C3 convertase that is further suppressed in the presence of CD55, forcing human IgG3 to act mainly through the alternative pathway.

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Targeting IgG3 Triggers Complement-Mediated Lysis of Decay-Accelerating Factor Expressing Tumor Cells through the Alternative Pathway Amplification Loop

Rösner

Lohse

Peipp

et al. 2014

The Journal of Immunology

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“…23,24 hIgG3 has, however, been found to be effective in mediating complement-dependent cytotoxicity, particularly against tumor targets with low epitope densities, which is probably due to the extraordinary long hinge of hIgG3 that may form a hexameric docking platform for C1q under those conditions. [37][38][39] Similarly, hIgG3 has been found highly efficient in protecting against pneumococcal infections in vivo, also through complement. 40,41 hIgG2 has a comparable binding pattern for the mouse Fc receptors as mIgG1, but with an estimated 5-to 50-fold lower affinity than mIgG1.…”

Section: Discussionmentioning

confidence: 99%

Affinity of human IgG subclasses to mouse Fc gamma receptors

Dekkers

Bentlage

Stegmann

et al. 2017

mAbs

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Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer halflife, which are completely or partly due to FcgR-mediated functions of the molecules. Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse FcgRs is available. The orthologous mouse and human FcgRs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse and human IgG subclasses to mouse FcgR. Human IgGs bound to mouse FcgR with remarkably similar binding strengths as we know from binding to human ortholog receptors, with relative affinities IgG3>IgG1>IgG4>IgG2 and FcgRI>>FcgRIV>FcgRIII>FcgRIIb. This suggests human IgG subclasses to have similar relative FcgRmediated biological activities in mice.

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“…Interestingly, IgG3 antibodies showed an increased ability to induce C1q binding and were more effective in Fc receptor binding than their IgG1 counterparts. Detailed analyses of IgG antibodies and their ability to activate the complement system demonstrated the superior efficacy of complement activation by the IgG3 isotype, particularly when epitope densities were lower [22,29]. Furthermore an IgG3 version of cetuximab was able to activate complement in contrast to the parental IgG1 antibody - with CD55 being the main regulator of IgG3-induced complement activation [30].…”

Section: Igg3mentioning

confidence: 99%

Antibody Isotypes for Tumor Immunotherapy

Kretschmer

Schwanbeck

Valerius

et al. 2017

Transfus Med Hemother

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Compared to the evolutionary diversity of antibody isotypes, the spectrum of currently approved therapeutic antibodies is biased to the human IgG1 isotype. Detailed studies into the different structures and functions of human isotypes have suggested that other isotypes than IgG1 may be advantageous for specific indications - depending on the complex interplay between the targeted antigen or epitope, the desired mode of action, the pharmacokinetic properties, and the biopharmaceutical considerations. Thus, it may be speculated that with the increasing number of antibodies becoming available against a broadening spectrum of target antigens, identification of the optimal antibody isotype for particular therapeutic applications may become critical for the therapeutic success of individual antibodies. Thus, investments into this rather unexplored area of antibody immunotherapy may provide opportunities for distinction in the increasingly busy ‘antibody space'. Therefore, IgG, IgA, IgE as well as IgM isotypes will be discussed in this review.

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An IgG3 switch variant of rituximab mediates enhanced complement‐dependent cytotoxicity against tumour cells with low CD20 expression levels

Cited by 23 publications

References 10 publications

Epidermal Growth Factor Receptor Targeting IgG3 Triggers Complement-Mediated Lysis of Decay-Accelerating Factor Expressing Tumor Cells through the Alternative Pathway Amplification Loop

Epidermal Growth Factor Receptor Targeting IgG3 Triggers Complement-Mediated Lysis of Decay-Accelerating Factor Expressing Tumor Cells through the Alternative Pathway Amplification Loop

Affinity of human IgG subclasses to mouse Fc gamma receptors

Antibody Isotypes for Tumor Immunotherapy

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