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

• Published in: Nature cancer Vol. 5; no. 10; pp. 1494 - 1514
• Main Authors: Carretero-Iglesia, Laura, Hall, Olivia J., Berret, Jérémy, Pais, Daniela, Estoppey, Carole, Chimen, Myriam, Monney, Thierry, Loyau, Jeremy, Dreyfus, Cyrille, Macoin, Julie, Perez, Cynthia, Menon, Vinu, Gruber, Isabelle, Laurendon, Amélie, Caro, Lydia N., Gudi, Girish S., Matsuura, Tomomi, van der Graaf, Piet H., Blein, Stanislas, Mbow, M. Lamine, Croasdale-Wood, Rebecca, Srivastava, Ankita, Dyson, Michael R., Matthes, Thomas, Kaya, Zeynep, Edwards, Claire M., Edwards, James R., Maiga, Sophie, Pellat-Deceunynck, Catherine, Touzeau, Cyrille, Moreau, Philippe, Konto, Cyril, Drake, Adam, Zhukovsky, Eugene A., Perro, Mario, Pihlgren, Maria
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2024
• Subjects: 13; 13/1; 13/21; 13/31; 14; 14/63; 631/154/51/1568; 631/67; 692/4028/67/1059/2325; 692/4028/67/1990/804; 692/4028/67/580; 82; 82/103; 82/47; 82/80; 82/83; ADP-ribosyl Cyclase 1 - immunology; Animals; Antigens, Neoplasm - immunology; B-Cell Maturation Antigen - immunology; Biomedical and Life Sciences; Cell Line, Tumor; Clinical Trials as Topic; Cytotoxicity, Immunologic - drug effects; Humans; Immunotherapy - methods; Life Sciences; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Escape - drug effects; Tumor Escape - immunology; Xenograft Model Antitumor Assays
• ISSN: 2662-1347
• DOI: 10.1038/s43018-024-00821-1

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. Perro and colleagues develop a CD3 + T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.