Antitumor activity of Antibody-Drug Conjugates targeting cancer-expressed EGFR in Preclinical Models
نویسندگان
چکیده
Background: The epidermal growth factor receptor (EGFR) plays a key role in the and survival of many human tumors epithelial origin. monoclonal antibody, 40H3, targeting overexpressed EGFR truncated form variant III (EGFRvIII) on tumor cells, was conjugated to small molecules with potent cytotoxic activity, generating five antibody-drug conjugates (ADCs). Their lethality for cells evaluated vitro vivo. Materials methods: ADC construction: Purified 40H3 antibody different payloads: two tubulin inhibitors, monomethyl auristatin E (MMAE) DM1, topoisomerase SN38 deruxtecan (DXd1) PBD dimer (SG-3199). Binding assay: binding affinity constants various 40H3-based ADCs were determined against His-tagged peptide loop (aa 287– 302) immobilized Ni-NTA biosensors Octet Red96 analyzer. Bystander Cocultured F98npEGFRvIII F98 treated media, free payload (SG-3199), 40H3-tesirine or IgG-tesirine at indicated concentrations. After 48 hours, labeled cetuximab-PE SYTOXTM Red viability dye then analyzed bystander killing by flow cytometry. In vivo studies: MDA-MB-468 BT-20 xenografts unmodified 40H3-tesirine. Tumor volumes mouse weights measured least three times weekly. Results: retained antigen activity antibody. They showed cytotoxicity panel EGFR-expressing including triple negative breast cancer lines. Cell correlated number sites conjugate (40H3-tesirine) most active agent it also exhibited not expressing EGFR. Moreover, vivo, models xenografts, treatment achieved complete remissions. Conclusions: is valid delivery toxic payloads. Among ADCs, highest effect toward No conflict interest.
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ژورنال
عنوان ژورنال: European Journal of Cancer
سال: 2022
ISSN: ['0959-8049', '1879-0852']
DOI: https://doi.org/10.1016/s0959-8049(22)01028-0