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

2024; Nature Portfolio; Linguagem: Inglês

10.1038/s43018-024-00821-1

2662-1347

Laura Carretero-Iglesia, O. Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jérémy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Pérez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia Nakopoulou, Girish Gudi, Tomomi Matsuura, Piet H. van der Graaf, Stanislas Blein, Moustapha Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R. Dyson, Thomas Matthes, Zeynep Kaya, Claire M. Edwards, James Edwards, Sophie Maïga, Catherine Pellat‐Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A. Zhukovsky, Mario Perro, Maria Pihlgren,

Immune Cell Function and Interaction

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.