Engineered antibody Fc variants with enhanced effector function

Lazar, Greg A.; Dang, Wei; Karki, Sher; Vafa, Omid; Peng, Judy S.; Hyun, Linus; Chan, Cheryl; Chung, Helen; Eivazi, Araz; Yoder, Sean C.; Vielmetter, Jost; Carmichael, David F.; Hayes, Robert J.; Dahiyat, Bassil I.

doi:10.1073/pnas.0508123103

Cited by 704 publications

(628 citation statements)

References 42 publications

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“…These Fc variants of either single (S239D or I332E), double (S239D/I332E) or triple (S239D/I332E/A330L) mutations demonstrated up to 169-fold enhanced interaction with human FcγRIIIa 71 . The Fc variants also showed enhanced binding ratio between activating FcRγIIIa and inhibitory FcγRIIb of up to 9-fold.…”

Section: Modulating Fcγriiia Interaction Through Fc Engineeringmentioning

confidence: 96%

“…With the use of computational structure-based design and high-throughput screening, a series of engineered Fc variants were generated 71 . These Fc variants of either single (S239D or I332E), double (S239D/I332E) or triple (S239D/I332E/A330L) mutations demonstrated up to 169-fold enhanced interaction with human FcγRIIIa 71 .…”

Section: Modulating Fcγriiia Interaction Through Fc Engineeringmentioning

confidence: 99%

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The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

mAbs

255

211

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Therapeutic monoclonal antibodies are the fastest growing class of biological therapeutics for the treatment of various cancers and inflammatory disorders. In cancer immunotherapy, some IgG1 antibodies rely on the Fc-mediated immune effector function, antibody-dependent cellular cytotoxicity (ADCC), as the major mode of action to deplete tumor cells. It is well-known that this effector function is modulated by the N-linked glycosylation in the Fc region of the antibody. In particular, absence of core fucose on the Fc N-glycan has been shown to increase IgG1 Fc binding affinity to the FcγRIIIa present on immune effector cells such as natural killer cells and lead to enhanced ADCC activity. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy. This review discusses the relevance of antibody core fucosylation to ADCC, different strategies to produce afucosylated antibodies, and an update of afucosylated antibody drugs currently undergoing clinical trials as well as those that have been approved.

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Section: Modulating Fcγriiia Interaction Through Fc Engineeringmentioning

confidence: 96%

Section: Modulating Fcγriiia Interaction Through Fc Engineeringmentioning

confidence: 99%

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Pereira

Chan

Lin

et al. 2018

mAbs

255

211

View full text Add to dashboard Cite

show abstract

“…By defined genetic engineering of the glycosylation pattern or the amino-acid sequence of the Fc part, antibody variants with markedly improved ADCC activity have been generated. 3,4 Different companies use different strategies: Roche (Basel, Switzerland), in cooperation with Glycart (Schlieren, Switzerland), has developed an improved, glyco-engineered CD20 antibody, termed GA101. 5 Two other antibodies directed to the lymphoma-associated antigens CD19 (XmAb5574) 6,7 and CD30 (XmAb2513), 8 developed by Xencor (Monrovia, CA, USA), carry the amino-acid exchanges S239D and I332E (SDIE modification).…”

Section: Introductionmentioning

confidence: 99%

Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia

et al. 2012

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The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.

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“…A fluorescence‐labeled, non‐neutralizing anti‐idiotypic antibody or an antibody with specificity for Fc 2, 3, 22 or a modified Fc region 38, 39, 40 can be used for detection. Selection of specific, high affinity reagents is essential for robust detection sensitivity.…”

Section: Considerations When Developing Flow Cytometry‐based Ro Assaysmentioning

confidence: 99%

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

Liang¹,

Schwickart²,

Schneider³

et al. 2015

Cytometry Part B Clinical

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Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry‐based RO method in support of biopharmaceutical drug development. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.

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Engineered antibody Fc variants with enhanced effector function

Cited by 704 publications

References 42 publications

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia

Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

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