ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells - Ecole Centrale de Nantes
Journal Articles Nature Cancer Year : 2024

ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells

Laura Carretero-Iglesia
  • Function : Author
  • PersonId : 1418423
  • IdRef : 189152931
Thierry Monney
Tomomi Matsuura
  • Function : Author
Michael Dyson
Thomas Matthes
Zeynep Kaya
  • Function : Author
Claire Edwards
James Edwards
Mario Perro

Abstract

Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3$^+$ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies.
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hal-04694485 , version 1 (18-09-2024)

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Laura Carretero-Iglesia, Olivia Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, et al.. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nature Cancer, In press, Online ahead of print. ⟨10.1038/s43018-024-00821-1⟩. ⟨hal-04694485⟩
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