Optimal combination of beneficial mutations for improved ADCC effector function of aglycosylated antibodies

Yoon, Hyun Woung; Jo, Migyeong; Ko, Sanghwan; Kwon, Hyeong Sun; Lim, Chung Su; Ko, Byoung Joon; Lee, Ji Chul; Jung, Sang Taek

doi:10.1016/j.molimm.2019.07.007

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…Aglycosylation of mAbs leads to decreased cytotoxic effector functions and is used when ADCC or CDC is unwanted in cases where neutralizing and agonistic/antagonistic properties are chosen as MoA. However, it has been demonstrated by different studies that some substitutions within the CH2 or CH3 domain (or both) do not completely prevent Fc interaction of aglycosylated antibodies with some FcγRs [142][143][144][145][146].…”

Section: Engineering Methods To Address the Fcγr Interactionmentioning

confidence: 99%

The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

Gogesch

Dudek

Zandbergen

et al. 2021

IJMS

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Since the approval of the first monoclonal antibody (mAb) in 1986, a huge effort has been made to guarantee safety and efficacy of therapeutic mAbs. As of July 2021, 118 mAbs are approved for the European market for a broad range of clinical indications. In order to ensure clinical efficacy and safety aspects, (pre-)clinical experimental approaches evaluate the respective modes of action (MoA). In addition to antigen-specificity including binding affinity and -avidity, MoA comprise Fc-mediated effector functions such as antibody dependent cellular cytotoxicity (ADCC) and the closely related antibody dependent cellular phagocytosis (ADCP). For this reason, a variety of cell-based assays have been established investigating effector functions of therapeutic mAbs with different effector/target-cell combinations and several readouts including Fcγ receptor (FcγR)-mediated lysis, fluorescence, or luminescence. Optimized FcγR-mediated effector functions regarding clinical safety and efficacy are addressed with modification strategies such as point mutations, altered glycosylation patterns, combination of different Fc subclasses (cross isotypes), and Fc-truncation of the mAb. These strategies opened the field for a next generation of therapeutic mAbs. In conclusion, it is of major importance to consider FcγR-mediated effector functions for the efficacy of therapeutic mAbs.

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Section: Engineering Methods To Address the Fcγr Interactionmentioning

confidence: 99%

The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

Gogesch

Dudek

Zandbergen

et al. 2021

IJMS

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“…constructed and screened a library of all mutations previously identified for both the glycosylated and aglycosylated Fc variants using their flow cytometric screening assay. 139 They obtained an aglycosylated Fc variant (Fc-HW86) that exhibited approximately 3–4-fold higher RIIIa binding and 2-fold enhanced ADCC activity compared with glycosylated trastuzumab. All mutations in this variant were derived from previously reported beneficial mutations for engineered aglycosylated Fc variants as opposed to engineered glycosylated Fc variants ( Table 3 ).…”

Section: Fc Engineering To Recruit Various Effector Functions In ...mentioning

confidence: 99%

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

Rashid

2022

mAbs

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Although several antibody fragments and antibody fragment-fusion proteins produced in Escherichia coli ( E. coli ) are approved as therapeutics for various human diseases, a full-length monoclonal or a bispecific antibody produced in E. coli has not yet been approved. The past decade witnessed substantial progress in expression of full-length antibodies in the E. coli cytoplasm and periplasm, as well as in cell-free expression systems. The equivalency of E. coli -produced aglycosylated antibodies and their mammalian cell-produced counterparts, with respect to biochemical and biophysical properties, including antigen binding, in vitro and in vivo serum stability, pharmacokinetics, and in vivo serum half-life, has been demonstrated. Extensive engineering of the Fc domain of aglycosylated antibodies enables recruitment of various effector functions, despite the lack of N -linked glycans. This review summarizes recent research, preclinical advancements, and clinical development of E. coli -produced aglycosylated therapeutic antibodies as monoclonal, bispecific, and antibody-drug conjugates for use in autoimmune, oncology, and immuno-oncology areas. Abbreviations: ADA Anti-drug antibody; ADCC Antibody-dependent cellular cytotoxicity; ADCP Antibody-dependent cellular phagocytosis; ADC Antibody-drug conjugate; aFc Aglycosylated Fc; AMD Age-related macular degeneration aTTP Acquired thrombotic thrombocytopenic purpura; BCMA B-cell maturation antigen; BLA Biologics license application; BsAb Bispecific antibody; C1q Complement protein C1q; CDC Complement-dependent cytotoxicity; CDCC Complement-dependent cellular cytotoxicity; CDCP Complement-dependent cellular phagocytosis; CEX Cation exchange chromatography; CFPS Cell-free protein expression; CHO Chinese Hamster Ovary; CH1-3 Constant heavy chain 1-3; CL Constant light chain; DLBCL Diffuse large B-cell lymphoma; DAR Drug antibody ratio; DC Dendritic cell; dsFv Disulfide-stabilized Fv; EU European Union; EGFR Epidermal growth factor receptor; E. coli Escherichia coli; EpCAM Epithelial cell adhesion molecule; Fab Fragment antigen binding; FACS Fluorescence activated cell sorting; Fc Fragment crystallizable; FcRn Neonatal Fc receptor; FcɣRs Fc gamma receptors; FDA Food and Drug Administration; FL-IgG Full-length immunoglobulin; Fv Fragment variable; FolRαa Folate receptor alpha; gFc Glycosylated Fc; GM-CSF Granulocyte macrophage-colony stimulating factor; GPx7 Human peroxidase 7; HCL Hairy cell leukemia; HIV Human immunodeficiency virusl; HER2 Human epidermal growth factor receptor 2; HGF Hepatocyte growth factor; HIC Hydrophobic interaction chromatography; HLA Human leukocyte antigen; IBs Inclusion bodies; IgG1-4 Immunoglobulin 1-4; IP Intraperitoneal; ITC Isothermal titration calorimetry; ITP Immune...

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“…Fc glycosylation is required for binding the low-affinity FcγR [ 30 , 31 ]. Generally, aglycosylation is thought to completely abrogate FcγR effector functions [ 32 , 33 ], but several aglycosylated Fc variants with intact FcγR effector function have been reported [ 34 , 35 , 36 ]. Altering the specific composition of the Fc glycan can increase the affinity for FcγR.…”

Section: Fc Engineering To Enhance Fc-effector Functionsmentioning

confidence: 99%

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

Horst

Nijhof

Mutis

et al. 2020

Cancers

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Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).

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Optimal combination of beneficial mutations for improved ADCC effector function of aglycosylated antibodies

Cited by 5 publications

References 28 publications

The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

Full-length recombinant antibodies from Escherichia coli : production, characterization, effector function (Fc) engineering, and clinical evaluation

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

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