Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Meyer, Saskia; Leusen, Jeanette H.W.; Boross, Péter

doi:10.4161/mabs.29670

Cited by 87 publications

(79 citation statements)

References 113 publications

(109 reference statements)

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“…The antibody may also potentially interfere with receptor internalization through the binding to TfR1 on cancer cells and FcγRs on the surface of immune cells in the tumor microenvironment, which would also result in iron deprivation and cancer cell death. Alternatively and non-exclusively, ch128.1 may induce cell death through eliciting antibody Fc effector functions such as ADCC, ADCP, and CDC, as observed with other antibody therapies (Bakema and van Egmond, 2014; Meyer et al, 2014; Nimmerjahn and Ravetch, 2007, 2008). ADCC can be mediated through activation of a variety of FcγR-bearing effector cells such as NK cells, monocytes/macrophages, dendritic cells, and PMN such as neutrophils (Clynes et al, 2000; Hernandez-Ilizaliturri et al, 2003; Hubert et al, 2011; Pincetic et al, 2014; Schmitz et al, 2002), while complement activation is triggered via binding of C1q, the recognition component of the initializing complex in the classical complement cascade (Meyer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1

Leoh

Daniels‐Wells

Martı́nez-Maza

et al. 2015

Molecular Immunology

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The transferrin receptor 1 (TfR1) is involved in cellular iron uptake and regulation of cell proliferation. The increased expression of TfR1 observed in malignant cells, compared to normal cells, together with its extracellular accessibility, make this receptor an attractive target for antibody-mediated cancer therapy. We have developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1), which shows antitumor activity against certain malignant B cells in vitro through TfR1 degradation and iron deprivation, and in vivo through a mechanism yet to be defined. To further explore potential mechanisms of action of ch128.1, we examined its ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC). We now report that ch128.1 is capable of mediating ADCC and CDC against malignant B cells, which is consistent with its ability to bind FcγRI, FcγRIIIa, and the complement component C1q. To delineate the residues involved in these effector functions, we developed a panel of three constructs with mutations in the lower hinge region and CH2 domain: 1) L234A/L235A, 2) P331S, and 3) L234A/L235A/P331S. The triple mutant consistently displayed a significant reduction in ADCC, while the L234A/L235A mutant exhibited less reduction in ADCC, and the P331S mutant did not show reduced ADCC. However, all three mutants exhibited impaired binding to FcγRI and FcγRIIIa. These results suggest that all three residues contribute to ADCC, although to different degrees. The P331S mutant showed drastically decreased C1q binding and abolished CDC, confirming the critical role of this residue in complement activation, while the other residues play a less important role in CDC. Our study provides insights into the effector functions of human IgG3 in the context of an antibody targeting TfR1.

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Section: Introductionmentioning

confidence: 99%

Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1

Leoh

Daniels‐Wells

Martı́nez-Maza

et al. 2015

Molecular Immunology

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“…The efficiency of anti-tumor mAb-therapy can be impeded by CRPs (83). Therefore, current studies are looking at the effect of CRP expression by cancer cells in inhibiting CDC (83,84). mCRPs Protectin, or CD59, inhibits MAC formation by binding to the C8 and C9 and, while it is universally expressed in normal cells, it is highly expressed in many kinds of cancer cells (85,86).…”

Section: Crpsmentioning

confidence: 99%

The dual role of complement in cancer and its implication in anti-tumor therapy

Kourtzelis¹,

Rafail

2016

Ann. Transl. Med.

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“…NKG2D [53]) may play a role. Likewise expression of mCRPs may protect tumor cells from CDC and thus lower the relative contribution of this elimination mechanism [54]. However, inhibitory effects may be overcome with Fc-engineered antibodies, as also suggested in the current study.…”

Section: Discussionmentioning

confidence: 81%

An Fc Double-Engineered CD20 Antibody with Enhanced Ability to Trigger Complement-Dependent Cytotoxicity and Antibody-Dependent Cell-Mediated Cytotoxicity

Wirt¹,

Rosskopf²,

Rösner³

et al. 2017

Transfus Med Hemother

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Background: Engineering of the antibody's fragment crystallizable (Fc) by modifying the amino acid sequence (Fc protein engineering) or the glycosylation pattern (Fc glyco-engineering) allows enhancing effector functions of tumor targeting antibodies. Here, we investigated whether complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of CD20 antibodies could be improved simultaneously by combining Fc protein engineering and glyco-engineering technologies. Methods and Results: Four variants of the CD20 antibody rituximab were generated: a native IgG1, a variant carrying the EFTAE modification (S267E/H268F/S324T/G236A/I332E) for enhanced CDC as well as glyco-engineered, non-fucosylated derivatives of both to boost ADCC. The antibodies bound CD20 specifically with similar affinity. Antibodies with EFTAE modification were more efficacious in mediating CDC, irrespective of fucosylation, than antibodies with wild-type sequences due to enhanced C1q binding. In contrast, non-fucosylated variants had an enhanced affinity to FcγRIIIA and improved ADCC activity. Importantly, the double-engineered antibody lacking fucose and carrying the EFTAE modification mediated both CDC and ADCC with higher efficacy than the native CD20 IgG1 antibody. Conclusion: Combining glyco-engineering and protein engineering technologies offers the opportunity to simultaneously enhance ADCC and CDC activities of therapeutic antibodies. This approach may represent an attractive strategy to further improve antibody therapy of cancer and deserves further evaluation.

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Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Cited by 87 publications

References 113 publications

Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1

Insights into the effector functions of human IgG3 in the context of an antibody targeting transferrin receptor 1

The dual role of complement in cancer and its implication in anti-tumor therapy

An Fc Double-Engineered CD20 Antibody with Enhanced Ability to Trigger Complement-Dependent Cytotoxicity and Antibody-Dependent Cell-Mediated Cytotoxicity

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