5MY6

Crystal structure of a HER2-Nb complex

Summary for 5MY6

• Entry DOI: 10.2210/pdb5my6/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Nanobody 2Rs15d, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: nanobody, her2, egfr family, radio-labeling, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 82036.73

Authors

Sterckx, Y.G.-J.,D'Huyvetter, M.,Devoogdt, N. (deposition date: 2017-01-25, release date: 2017-08-09, Last modification date: 2024-10-23)

Primary citation

D'Huyvetter, M.,De Vos, J.,Xavier, C.,Pruszynski, M.,Sterckx, Y.G.J.,Massa, S.,Raes, G.,Caveliers, V.,Zalutsky, M.R.,Lahoutte, T.,Devoogdt, N.
(131)I-labeled Anti-HER2 Camelid sdAb as a Theranostic Tool in Cancer Treatment.
Clin. Cancer Res., 23:6616-6628, 2017

PubMed Abstract: Camelid single-domain antibody-fragments (sdAb) have beneficial pharmacokinetic properties, and those targeted to HER2 can be used for imaging of HER2-overexpressing cancer. Labeled with a therapeutic radionuclide, they may be used for HER2-targeted therapy. Here, we describe the generation of a I-labeled sdAb as a theranostic drug to treat HER2-overexpressing cancer. Anti-HER2 sdAb 2Rs15d was labeled with I using [I]SGMIB and evaluated Biodistribution was evaluated in two HER2 murine xenograft models by micro-SPECT/CT imaging and at necropsy, and under challenge with trastuzumab and pertuzumab. The therapeutic potential of [I]SGMIB-2Rs15d was investigated in two HER2 tumor mouse models. A single-dose toxicity study was performed in mice using unlabeled [I]SGMIB-sdAb at 1.4 mg/kg. The structure of the 2Rs15d-HER2 complex was determined by X-ray crystallography. [I]SGMIB-2Rs15d bound specifically to HER2 cells ( = 4.74 ± 0.39 nmol/L). High and specific tumor uptake was observed in both BT474/M1 and SKOV-3 tumor xenografted mice and surpassed kidney levels by 3 hours. Extremely low uptake values were observed in other normal tissues at all time points. The crystal structure revealed that 2Rs15d recognizes HER2 Domain 1, consistent with the lack of competition with trastuzumab and pertuzumab observed [I]SGMIB-2Rs15d alone, or in combination with trastuzumab, extended median survival significantly. No toxicity was observed after injecting [I]SGMIB-2Rs15d. These findings demonstrate the theranostic potential of [I]SGMIB-2Rs15d. An initial scan using low radioactive [*I]SGMIB-2Rs15d allows patient selection and dosimetry calculations for subsequent therapeutic [I]SGMIB-2Rs15d and could thereby impact therapy outcome on HER2 breast cancer patients. .

PubMed: 28751451
DOI: 10.1158/1078-0432.CCR-17-0310

Experimental method

X-RAY DIFFRACTION (2.246 Å)