IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions

Lee, Chang Han; Romain, Gabrielle; Yan, Wang; Watanabe, Makiko; Charab, Wissam; Todorova, Biliana; Lee, Jiwon; Triplett, Kendra; Donkor, Moses; Lungu, Oana I.; Lux, Anja; Marshall, Nicholas; Lindorfer, Margaret A.; Goff, Odile Richard-Le; Balbino, Bianca; Kang, Tae Hyun; Tanno, Hidetaka; Delidakis, George; Alford, Corrine; Taylor, Ronald P.; Nimmerjahn, Falk; Varadarajan, Navin; Bruhns, Pierre; Zhang, Yan Jessie; Georgiou, George

doi:10.1038/ni.3770

Cited by 116 publications

(122 citation statements)

References 59 publications

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“…For each run, a bovine serum albumin (BSA)-coupled surface was used to subtract non-specific receptor binding. The K D of each monoclonal antibody was calculated by fitting 2:1 bivalent analyte models (A+2B<->AB+B<->AB 2 ) to the data using BIAevaluation 3.2 software (GE Healthcare) in accordance with previously reported analyses (40) and averaged from three independent experiments.…”

Section: Methodsmentioning

confidence: 99%

Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

McDaniel

Pero

Voss

et al. 2018

Cancer Immunol Immunother

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A better understanding of antitumor immune responses is the key to advancing the field of cancer immunotherapy. Endogenous immunity in cancer patients, such as circulating anticancer antibodies or tumor-reactive B cells, has been historically yet incompletely described. Here, we demonstrate that tumor-draining (sentinel) lymph node (SN) is a rich source for tumor-reactive B cells that give rise to systemic IgG anticancer antibodies circulating in the bloodstream of breast cancer patients. Using a synergistic combination of high-throughput B-cell sequencing and quantitative immunoproteomics, we describe the prospective identification of tumor-reactive SN B cells (based on clonal frequency) and also demonstrate an unequivocal link between affinity-matured expanded B-cell clones in the SN and antitumor IgG in the blood. This technology could facilitate the discovery of antitumor antibody therapeutics and conceivably identify novel tumor antigens. Lastly, these findings highlight the unique and specialized niche the SN can fill in the advancement of cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

McDaniel

Pero

Voss

et al. 2018

Cancer Immunol Immunother

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“…Thus, C3b deposition triggered by target cell-bound antibodies was shown to hinder the interaction of the antibody with FcγRIIIa on NK cells, resulting in diminished ADCC [24]. Therefore, efficient complement fixation is beneficial when induction of CDC, complement-dependent cell-mediated cytotoxicity (CDCC), or complement-dependent cellular phagocytosis (CDCP) is possible [26]. However, when not, it may even impede other effector functions and potentially diminish therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Lee and colleagues [26] described novel Fc mutations enabling selective binding to C1q without concomitant engagement of Fcγ receptors. The engineered Fc domains were introduced into the rituximab antibody and potently triggered CDC.…”

Section: Enhancing Cdc Activitymentioning

confidence: 99%

Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy

Kellner

Otte

Cappuzzello

et al. 2017

Transfus Med Hemother

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In the last two decades, monoclonal antibodies have revolutionized the therapy of cancer patients. Although antibody therapy has continuously been improved, still a significant number of patients do not benefit from antibody therapy. Therefore, rational optimization of the antibody molecule by Fc engineering represents a major area of translational research to further improve this potent therapeutic option. Monoclonal antibodies are able to trigger a variety of effector mechanisms. Especially Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement- dependent cytotoxicity (CDC) are considered important in antibody therapy of cancer. Novel mechanistic insights into the action of monoclonal antibodies allowed the development of various Fc engineering approaches to modulate antibodies' effector functions. Strategies in modifying the Fc glycosylation profile (Fc glyco-engineering) or approaches in engineering the protein backbone (Fc protein engineering) have been intensively evaluated. In the current review, Fc engineering strategies resulting in improved ADCC, ADCP and CDC activity are summarized and discussed.

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“…Microfluidic devices have the potential to dynamically monitor cell-cell interaction in a high-throughput manner in combination with live cell microscopy. TIMING (Figure 1E), a microwell-based platform, was reported to able to dynamically monitor cell-cell interaction, cytotoxicity, cell motility and cell survival simultaneously [77–79]. Additionally, it can integrate real-time cytokine profiling by bead-based cytokine sensors [80] or gene expression profiling by single cell retrieval via micromanipulator [81] due to the non-destructive feature of this assay.…”

Section: Integrated Platforms To Monitor Dynamic T-cell Behavior and mentioning

confidence: 99%

Single-cell technologies for profiling T cells to enable monitoring of immunotherapies

Varadarajan

2018

Current Opinion in Chemical Engineering

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Immunotherapy relies on the reinvigoration of immune system to combat diseases and has transformed the landscape of cancer treatments. Clinical trials using immune checkpoint inhibitors (ICI), and adoptive transfer of genetically modified T cells have demonstrated durable remissions in subsets of cancer patients. A comprehensive understanding of the polyfunctionality of T lymphocytes in ICI or adoptive cell transfer (ACT), at single-cell resolution, will quantify T-cell properties that are essential for therapeutic benefit. We briefly highlight several emerging integrated single-cell technologies focusing on the profiling of multiple properties/functionalities of T cells. We envision that these tools have the potential to provide valuable experimental and clinical insights on T-cell biology, and eventually pave the road for the discovery of surrogate T-cell biomarkers for immunotherapy.

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IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions

Cited by 116 publications

References 59 publications

Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node

Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy

Single-cell technologies for profiling T cells to enable monitoring of immunotherapies

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