Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Wakefield, Devin L.; Golfetto, Ottavia; Jorand, Raphaël; Biswas, Sunetra; Meyer, Kassondra; Avery, Kendra N.; Zer, Cindy; Cacao, Eliedonna E.; Tobin, Steven J.; Talisman, Ian Jamie; Williams, John C.; Jovanović-Talisman, Tijana

doi:10.3389/fmed.2023.1064242

Cited by 2 publications

(1 citation statement)

References 68 publications

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“…. Localization of HER2 protein was predicted to be extracellular in all the cases, which is consistent with the previously reported literature (Jeong et al, 2017;Wakefield et al, 2023). In all the cases except 6 and 8, the mutated proteins were slightly acidic, just like normal proteins, with pI ranging between 5.48 and 5.87.…”

Section: Prediction Of Snps Effect On 3d Structuresupporting

confidence: 90%

In-Silico Characterization of Human Her2 Gene to Predict the Breast Cancer Associated Biomarkers

MUCCEE,

RAZZAQ,

KHATOON

et al. 2023

Biol Clin Sci Res J

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HER2 gene hyperactivation is responsible for the incidence of invasive breast cancer (BC). It leads to over expression of HER2 receptors in breast cells resulting in abnormal receptor dimerization and signal transduction cascade initiation. It ultimately causes uncontrolled proliferation of breast cells. Therefore, this is the most susceptible target gene for BC treatment. HER2 gene transcript with accession ID ENST00000269571.10 was selected for association analysis in present study. A total of ten single nucleotide polymorphisms (SNPs) of gene were analyzed using in-silico tools like CELLO, PROTPARAM, SOPMA, and SWISSMODEL. These tools helped in determining the effect of variants on sub-cellular localization, physiochemical properties, and secondary (2D) and tertiary (3D) structures of mutated proteins. Variants rs1249755832, rs769703068, rs1567913219, and rs1213602748 altered the localization of mutated proteins. SNPs rs1213602748, rs769703068, and rs1249755832 considerably changed the isoelectric point (pI), extinction coefficient, instability index, aliphatic index, and GRAVY. Variant rs769703068 caused a change in all four properties of the 2D structure, i.e., alpha helix, extended strand, beta-turn, and random coil. Polymorphisms that caused a significant deviation in 3D configuration were rs769703068, rs144434331, and rs146177313. These variants can be recommended as biomarkers for HER2+ BC cell diagnosis.

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Section: Prediction Of Snps Effect On 3d Structuresupporting

confidence: 90%

In-Silico Characterization of Human Her2 Gene to Predict the Breast Cancer Associated Biomarkers

MUCCEE,

RAZZAQ,

KHATOON

et al. 2023

Biol Clin Sci Res J

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Antibody-target binding quantification in living tumors using macroscopy fluorescence lifetime Forster resonance energy transfer imaging (MFLI FRET)

Yuan,

Pandey,

Verma

et al. 2024

Visualizing and Quantifying Drug Distribution in Tissue VIII

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Emergent breast tumor resistance and tumor microenvironment (TME) heterogeneity can lead to decreased drug delivery efficacy, resulting in therapeutic failure. Preclinical molecular imaging is a crucial tool in the advancement of targeted therapeutics for supporting the development of new drugs but also to elucidate factors hampering optimal drug delivery. However, noninvasive tumor imaging modalities that can quantify drug-target engagement, which is critical for therapeutic actuation, are still lacking. We have demonstrated the utility of macroscopic fluorescence lifetime Forster's Resonance Energy Transfer (MFLI FRET)-based optical imaging to measure labeled trastuzumab (TZM)-human epidermal growth factor receptor (HER2) binding in human HER2+ cell lines and breast tumor xenograft mice models. We have established a clinically relevant TZM antibody drug containing the Meditope (MDT) peptide conjugated to near-infrared (NIR) dyelabeled FRET pairs, that retain full HER2 binding capability. Herein, we demonstrate FRET measurements using MFLI in vivo imaging platform to measure the ability of MDT-TZM to bind HER2 in living breast tumor xenografts. HER2+ AU565 breast tumor xenografts bearing nude mice were injected retro-orbitally with TZM (NHS-conjugated) or MDT-TZM labeled with AlexaFluor700 (donor) and AlexaFluor750 (acceptor) and MFLIFRET imaging was performed 24 h and 48 h post-injection. Preliminary data suggest that MDT-TZM shows higher uniform and consistent FRET signal compared to TZM, suggesting increased efficacy of TZM-MDT-HER2 binding. Also staggered injections of donor and acceptor MDT-TZM may be optimal for quantifying MDT-TZM using MFLIFRET compared to single injections.

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Using quantitative single molecule localization microscopy to optimize multivalent HER2-targeting ligands

Cited by 2 publications

References 68 publications

In-Silico Characterization of Human Her2 Gene to Predict the Breast Cancer Associated Biomarkers

In-Silico Characterization of Human Her2 Gene to Predict the Breast Cancer Associated Biomarkers

Antibody-target binding quantification in living tumors using macroscopy fluorescence lifetime Forster resonance energy transfer imaging (MFLI FRET)

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