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<p>Belantamab mafodotin, an antibody–drug conjugate (ADC), has shown strong efficacy in multiple myeloma. It comprises a humanized anti-B-cell maturation antigen (BCMA) IgG1 monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Ocular-related adverse events, particularly corneal events, have been reported with MMAF-containing ADCs, including belantamab mafodotin, through unknown mechanisms. This study investigated the mechanism of uptake and cytotoxicity with belantamab mafodotin in non-BCMA-expressing primary human corneal epithelial cells (HCEC), renal proximal tubule cells (RPTEC) to better understand the etiology of corneal events. ADC uptake into HCEC and RPTEC was concentration and time dependent. Results indicated uptake and traffic into the endocytic pathway, and ADC cleavage to release cys-mcMMAF leading to breakdown of the microtubule network and apoptosis, with greater uptake and cytotoxicity in HCEC versus RPTEC. ADC uptake was significantly reduced (~ 23%) following treatment with the macropinocytosis inhibitor 5-(N-Ethyl-N-isopropyl)amiloride. Co-treatment with endocytic pathway inhibitors nystatin or chlorpromazine also reduced ADC uptake, while siRNA depletion of specific endocytic pathways showed no consistent effects on uptake in HCEC. These in vitro data indicate BCMA-independent macropinocytosis plays a role in belantamab mafodotin uptake by HCEC, leading to cell death consistent with the inhibition of tubulin polymerization, the mechanism of MMAF toxicity. However, the precise mechanism of uptake requires further research. Treatment of cells with human immunoglobulin solution reduced belantamab mafodotin uptake in HCEC, protected nuclei count, and significantly reduced apoptosis and should be explored further.</p> Graphical Abstract <p>•&#xa0;<i>In vitro</i>, belantamab mafodotin (ADC) undergoes uptake into primary human corneal epithelial cells in a concentration/time-dependent manner, leading to apoptosis of the cells and thereby ocular adverse events in patients.</p> <p>• Co-treatment of ADC with macropinocytosis inhibitor 5-(N-Ethyl-N-isopropyl)amiloride led to decreased uptake, suggesting macropinocytosis involvement.</p> <p>• Treatment consistent with IVIG led to decreased ADC uptake and cytoprotection, and should be explored further</p> <p></p>

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Mechanism of uptake and toxicity of a BCMA antibody drug conjugate with a MMAF payload by nonantigen expressing cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Carla Newman,
  • Chloe Taylor,
  • Gurpreet Sohanpal,
  • Tanja Högg,
  • James Kennedy,
  • Eliot McKinley,
  • Elena Koudouna,
  • Edward J. Sayers,
  • Arwyn T. Jones,
  • Peter Watson,
  • Lucinda Weir

摘要

Belantamab mafodotin, an antibody–drug conjugate (ADC), has shown strong efficacy in multiple myeloma. It comprises a humanized anti-B-cell maturation antigen (BCMA) IgG1 monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Ocular-related adverse events, particularly corneal events, have been reported with MMAF-containing ADCs, including belantamab mafodotin, through unknown mechanisms. This study investigated the mechanism of uptake and cytotoxicity with belantamab mafodotin in non-BCMA-expressing primary human corneal epithelial cells (HCEC), renal proximal tubule cells (RPTEC) to better understand the etiology of corneal events. ADC uptake into HCEC and RPTEC was concentration and time dependent. Results indicated uptake and traffic into the endocytic pathway, and ADC cleavage to release cys-mcMMAF leading to breakdown of the microtubule network and apoptosis, with greater uptake and cytotoxicity in HCEC versus RPTEC. ADC uptake was significantly reduced (~ 23%) following treatment with the macropinocytosis inhibitor 5-(N-Ethyl-N-isopropyl)amiloride. Co-treatment with endocytic pathway inhibitors nystatin or chlorpromazine also reduced ADC uptake, while siRNA depletion of specific endocytic pathways showed no consistent effects on uptake in HCEC. These in vitro data indicate BCMA-independent macropinocytosis plays a role in belantamab mafodotin uptake by HCEC, leading to cell death consistent with the inhibition of tubulin polymerization, the mechanism of MMAF toxicity. However, the precise mechanism of uptake requires further research. Treatment of cells with human immunoglobulin solution reduced belantamab mafodotin uptake in HCEC, protected nuclei count, and significantly reduced apoptosis and should be explored further.

Graphical Abstract

• In vitro, belantamab mafodotin (ADC) undergoes uptake into primary human corneal epithelial cells in a concentration/time-dependent manner, leading to apoptosis of the cells and thereby ocular adverse events in patients.

• Co-treatment of ADC with macropinocytosis inhibitor 5-(N-Ethyl-N-isopropyl)amiloride led to decreased uptake, suggesting macropinocytosis involvement.

• Treatment consistent with IVIG led to decreased ADC uptake and cytoprotection, and should be explored further