作者
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 R. Edwards,Sophie Maïga,Catherine Pellat‐Deceunynck,Cyrille Touzeau,Philippe Moreau,Cyril Konto,Adam Drake,Eugene A. Zhukovsky,Mario Perro,Maria Pihlgren
摘要
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.