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A CD3+ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma is developed, cytotoxicity in patient-derived samples and murine models is demonstrated and an innovative quantitative systems pharmacology model is developed.
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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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@article{Srivastava20242001,
title = {ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells},
author = {Ankita Srivastava and Michael R. Dyson and Laura Carretero-Iglesia and O. Hall and Jérémy Berret and Daniela Pais and Carole Estoppey and Myriam Chimen and Thierry Monney and Jérémy Loyau and Cyrille Dreyfus and Julie Macoin and Cynthia Pérez and Vinu Menon and Isabelle Gruber and Amélie Laurendon and Lydia Nakopoulou and Girish Gudi and Tomomi Matsuura and Piet H. van der Graaf and Stanislas Blein and Moustapha Mbow and Rebecca Croasdale-Wood and Thomas Matthes and Zeynep Kaya and Claire M. Edwards and James Edwards and Sophie Maïga and Catherine Pellat‐Deceunynck and Cyrille Touzeau and Philippe Moreau and Cyril Konto and Adam Drake and Eugene A. Zhukovsky and Mario Perro and Maria Pihlgren},
journal = {Nature Cancer},
year = {2024},
doi = {10.1038/s43018-024-00821-1},
url = {https://doi.org/10.1038/s43018-024-00821-1}
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