Structural Basis for Treating Tumor Necrosis Factor α (TNFα)-associated Diseases with the Therapeutic Antibody Infliximab

Liang, Shuaiyi; Dai, Jing; Hou, Sheng; Su, Lishu; Zhang, David; Guo, Haipeng; Hu, Shi; Wang, Hao; Rao, Zihe; Guo, Yajun; Lou, Zhiyong

doi:10.1074/jbc.m112.433961

Cited by 92 publications

(122 citation statements)

References 54 publications

(47 reference statements)

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“…2013) with the light chains of the Fab fragment of a murine immunoglobulin (PDB_ID: 1IGT) (Harris et al. 1997).…”

Section: Resultsmentioning

confidence: 99%

“…Then, we aligned the sequences of the heavy chains of the Fab fragment of the infliximab (4G3Y) (Liang et al. 2013) with the heavy chains of the Fab fragment of the murine immunoglobulin 1IGT (Harris et al. 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The sites of interaction and the AA residues responsible for the binding of the Fab fragment to the antigen were recently reported for the first time for infliximab (Liang et al. 2013). Crystallography revealed that there is only one TNF α /infliximab–Fab complex in one asymmetric unit.…”

Section: Introductionmentioning

confidence: 99%

“…The E‐F loop is critical in determining the high affinity and specificity of the binding of infliximab to TNF α versus TNF β (Liang et al. 2013). …”

Section: Introductionmentioning

confidence: 99%

“…2000), and the infliximab Fab fragment in complex with TNF α (see 4G3Y) (Liang et al. 2013) are available on the protein data bank, the influence of the Fc fucosylation on the molecular interactions between mAbs and Fc receptors have never been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF α‐related immunological diseases. Other than neutralizing TNF α, these IgG1 antibodies exert Fc receptor‐mediated effector functions such as the complement‐dependent cytotoxicity (CDC) and antibody‐dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand‐binding interaction of these mAbs used in TNF α‐related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen‐binding fragment (Fab) portions of infliximab, complexed with TNF α (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcγ RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcγ RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab‐TNF α interactions, we found that in the absence of fucosylation the Fc–mAb domain and Fcγ RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcγ RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions.

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“…2013) with the light chains of the Fab fragment of a murine immunoglobulin (PDB_ID: 1IGT) (Harris et al. 1997).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The E‐F loop is critical in determining the high affinity and specificity of the binding of infliximab to TNF α versus TNF β (Liang et al. 2013). …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Pierri

Bossis

Punzi

et al. 2016

Pharmacology Res & Perspec

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Mechanism of Action for Therapeutic Antibodies

Zhou

Marks

2016

Biosimilars of Monoclonal Antibodies

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How Biorecognition Affects the Electronic Properties of Reduced Graphene Oxide in Electrolyte‐Gated Transistor Immunosensors

Sensi,

de Oliveira,

Berto

et al. 2024

Adv Funct Materials

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Ambipolar electrolyte‐gated transistors (EGTs) based on reduced graphene oxide (rGO) have been demonstrated as ultra‐sensitive and highly specific immunosensors. However, the physics and chemistry ruling the device operation are still not fully unraveled. In this work, the aim is to elucidate the nature of the observed sensitivity of the device. Toward this aim, a physical–chemical model that, coupled with the experimental characterization of the rGO‐EGT, allows one to quantitatively correlate the biorecognition events at the gate electrode and the electronic properties of rGO‐EGT is proposed. The equilibrium of biorecognition occurring at the gate electrode is shown to determine the apparent charge neutrality point (CNP) of the rGO channel. The multiparametric analysis of the experimental transfer characteristics of rGO‐EGT reveals that the recognition events modulate the CNP voltage, the excess carrier density Δn, and the quantum capacitance of rGO. This analysis also explains why hole and electron carrier mobilities, interfacial capacitance, the curvature of the transfer curve, and the transconductances are insensitive to the target concentration. The understanding of the mechanisms underlying the transistor transduction of the biorecognition events is key for the interpretation of the response of the rGO‐EGT immunosensors and to guide the design of novel and more sensitive devices.

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Structural Basis for Treating Tumor Necrosis Factor α (TNFα)-associated Diseases with the Therapeutic Antibody Infliximab

Cited by 92 publications

References 54 publications

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Molecular modeling of antibodies for the treatment of TNFα‐related immunological diseases

Mechanism of Action for Therapeutic Antibodies

How Biorecognition Affects the Electronic Properties of Reduced Graphene Oxide in Electrolyte‐Gated Transistor Immunosensors

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