Functional antibody characterization via direct structural analysis and information‐driven protein–protein docking

Depetris, Rafael S.; Lü, Dan; Polonskaya, Zhanna; Zhang, Zhikai; Luna, Xenia; Tankard, Amari; Kolahi, Pegah; Drummond, Michael L.; Williams, Chris; Ebert, Maximilian; Patel, Jeegar; Poyurovsky, Masha V.

doi:10.1002/prot.26280

Cited by 5 publications

(2 citation statements)

References 85 publications

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“…Additionally, they stopped the development of renal cancer cells that express VEGF-C by inhibiting NRP2 signaling [ 40 ]. VEGFR2 is the target of the fully human antibody KD035, which prevented the activation of VEGFR2 by VEGF-A and VEGF-C [ 41 ].…”

Section: Correlation Of Ovarian Cancer and Vegfmentioning

confidence: 99%

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Mishra,

Chattaraj,

Mishra

et al. 2023

Pharmaceuticals

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Cancer is one of the diseases that causes a high mortality as it involves unregulated and abnormal cell growth proliferation that can manifest in any body region. One of the typical ovarian cancer symptoms is damage to the female reproductive system. The death rate can be reduced through early detection of the ovarian cancer. Promising probes that can detect ovarian cancer are suitable aptamers. Aptamers, i.e., so-called chemical antibodies, have a strong affinity for the target biomarker and can typically be identified starting from a random library of oligonucleotides. Compared with other probes, ovarian cancer targeting using aptamers has demonstrated superior detection effectiveness. Various aptamers have been selected to detect the ovarian tumor biomarker, vascular endothelial growth factor (VEGF). The present review highlights the development of particular aptamers that target VEGF and detect ovarian cancer at its earliest stages. The therapeutic efficacy of aptamers in ovarian cancer treatment is also discussed.

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Section: Correlation Of Ovarian Cancer and Vegfmentioning

confidence: 99%

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Mishra,

Chattaraj,

Mishra

et al. 2023

Pharmaceuticals

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“…Protein antibodies are high information content materials; the information resides in their amino acid sequence. Antibody–antigen binding is understood from X-ray crystal structures, site-directed mutagenesis, and in silico studies of antibody–antigen complexes . SAs on the other hand are low information content materials.…”

Section: Introductionmentioning

confidence: 99%

Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy

Koide,

Kiyokawa,

Okishima

et al. 2023

J. Am. Chem. Soc.

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High-mobility group box 1 (HMGB1) is a multifunctional protein. Upon injury or infection, HMGB1 is passively released from necrotic and activated dendritic cells and macrophages, where it functions as a cytokine, acting as a ligand for RAGE, a major receptor of innate immunity stimulating inflammation responses including the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Blocking the HMGB1/RAGE axis offers a therapeutic approach to treating these inflammatory conditions. Here, we describe a synthetic antibody (SA), a copolymer nanoparticle (NP) that binds HMGB1. A lightly cross-linked N-isopropylacrylamide (NIPAm) hydrogel copolymer with nanomolar affinity for HMGB1 was selected from a small library containing trisulfated 3,4,6S-GlcNAc and hydrophobic N-tert-butylacrylamide (TBAm) monomers. Competition binding experiments with heparin established that the dominant interaction between SA and HMGB1 occurs at the heparin-binding domain. In vitro studies established that anti-HMGB1-SA inhibits HMGB1-dependent ICAM-1 expression and ERK phosphorylation of HUVECs, confirming that SA binding to HMGB1 inhibits the proteins’ interaction with the RAGE receptor. Using temporary middle cerebral artery occlusion (t-MCAO) model rats, anti-HMGB1-SA was found to accumulate in the ischemic brain by crossing the blood–brain barrier. Significantly, administration of anti-HMGB1-SA to t-MCAO rats dramatically reduced brain damage caused by cerebral ischemia/reperfusion. These results establish that a statistical copolymer, selected from a small library of candidates synthesized using an “informed” selection of functional monomers, can yield a functional synthetic antibody. The knowledge gained from these experiments can facilitate the discovery, design, and development of a new category of drug.

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Functional antibody characterization via direct structural analysis and information‐driven protein–protein docking

et al. 2021

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Detailed description of the mechanism of action of the therapeutic antibodies is essential for the functional characterization and future optimization of potential clinical agents. We recently developed KD035, a fully human antibody targeting vascular endothelial growth factor receptor 2 (VEGFR2). KD035 blocked VEGF-A, and VEGF-C-mediated VEGFR2 activation, as demonstrated by the in vitro binding and competition assays and functional cellular assays. Here, we report a computational model of the complex between the variable fragment of KD035 (KD035(Fv)) and the domains 2 and 3 of the extracellular portion of VEGFR2 (VEGFR2(D2-3)). Our modeling was guided by a priori experimental information including the X-ray structures of KD035 and related antibodies, binding assays, target domain mapping and comparison of KD035 affinity for VEGFR2 from different species. The accuracy of the model was assessed by molecular dynamics simulations, and subsequently validated by mutagenesis and binding analysis. Importantly, the steps followed during the generation of this model can set a precedent for future in silico efforts aimed at the accurate description of the antibody-antigen and more broadly protein-protein complexes.

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Functional antibody characterization via direct structural analysis and information‐driven protein–protein docking

Cited by 5 publications

References 85 publications

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Aptamers Versus Vascular Endothelial Growth Factor (VEGF): A New Battle against Ovarian Cancer

Design of an Anti-HMGB1 Synthetic Antibody for In Vivo Ischemic/Reperfusion Injury Therapy

Functional antibody characterization via direct structural analysis and information‐driven protein–protein docking

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