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<p>The humanization of mouse monoclonal antibodies targeting tumor antigens allows for the safe and repeated administration of therapeutic antibodies to humans. Previously, we reported on mouse monoclonal antibody 40H3 and its reactivity with a conformational epitope exposed on EGFR when expressed by cancer cells. To advance 40H3 toward the clinic, we generated various humanized variants, evaluated each for binding to either the peptide epitope or intact cells, and now report on the lead candidate, A10, which exhibited the strongest cell binding activity. A10 binding was characterized in detail on a collection of cancer cell lines each harboring different EGFR mutations or overexpressed EGFR and, where appropriate, compared with 40H3 or Cetuximab. A structural study of the A10 Fab with bound peptide revealed that A10 was unlikely to react with either tethered or untethered forms of wild type EGFR, as the accessibility to the peptide epitope by A10 is EGFR conformational dependent. As a proof of concept to produce therapeutic agents from A10, an antibody drug conjugate (ADC) with monomethyl-auristatin-E (MMAE) was generated and proved potently cytotoxic for cells displaying high levels of EGFR.</p>

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Targeting cancer expressed EGFR with a humanized monoclonal antibody

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月28日

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  • Tamara G. Fernandes Costa,
  • Robert Sarnovsky,
  • Jingyu Zhan,
  • Carolyn A. Maslanka,
  • Ifechukwu Obiorah,
  • Di Xia,
  • David FitzGerald,
  • Antonella Antignani

摘要

The humanization of mouse monoclonal antibodies targeting tumor antigens allows for the safe and repeated administration of therapeutic antibodies to humans. Previously, we reported on mouse monoclonal antibody 40H3 and its reactivity with a conformational epitope exposed on EGFR when expressed by cancer cells. To advance 40H3 toward the clinic, we generated various humanized variants, evaluated each for binding to either the peptide epitope or intact cells, and now report on the lead candidate, A10, which exhibited the strongest cell binding activity. A10 binding was characterized in detail on a collection of cancer cell lines each harboring different EGFR mutations or overexpressed EGFR and, where appropriate, compared with 40H3 or Cetuximab. A structural study of the A10 Fab with bound peptide revealed that A10 was unlikely to react with either tethered or untethered forms of wild type EGFR, as the accessibility to the peptide epitope by A10 is EGFR conformational dependent. As a proof of concept to produce therapeutic agents from A10, an antibody drug conjugate (ADC) with monomethyl-auristatin-E (MMAE) was generated and proved potently cytotoxic for cells displaying high levels of EGFR.