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

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Title: ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells
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
Contributors: Ichnos Glenmark Innovation, Certara UK Limited, Hôpitaux Universitaires de Genève (HUG), University of Oxford, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Site de Recherche Intégrée sur le Cancer - Imaging and Longitudinal Investigations to Ameliorate Decision-making (SIRIC-ILIAD), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-ARRONAX - (GIP) Groupement d'Intérêt Public Saint-Herblain (Institut de Recherche Public)-Nantes Université (Nantes Univ)-NANTES UNIVERSITÉ - École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ), Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes)
Source: Nat Cancer
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Cytotoxicity, Immunologic, ADP-ribosyl Cyclase 1 / immunology, T-Lymphocytes, Tumor Escape / drug effects, [SDV.CAN]Life Sciences [q-bio]/Cancer, Multiple Myeloma / immunology, Lymphocyte Activation / drug effects, Multiple Myeloma / drug therapy, 616.07, Lymphocyte Activation, Article, Mice, Cytotoxicity, Immunologic / drug effects, Antigens, Neoplasm, Cell Line, Tumor, T-Lymphocytes / drug effects, Animals, Humans, Tumor Escape / immunology, B-Cell Maturation Antigen, Clinical Trials as Topic, Lymphocyte Activation / immunology, T-Lymphocytes / immunology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ADP-ribosyl Cyclase 1, Xenograft Model Antitumor Assays, Antigens, Neoplasm / immunology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunotherapy / methods, Tumor Escape, Immunotherapy, B-Cell Maturation Antigen / immunology, Multiple Myeloma
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 2662-1347
DOI: 10.1038/s43018-024-00821-1
Access URL: https://pubmed.ncbi.nlm.nih.gov/39261676
https://ora.ox.ac.uk/objects/uuid:c3622b6e-528d-4447-a487-c45f54ddb9e6
https://doi.org/10.1038/s43018-024-00821-1
Rights: CC BY
Accession Number: edsair.doi.dedup.....d2c84859322b1df1df27782644ee3f8e
Database: OpenAIRE
Description
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.
ISSN:26621347
DOI:10.1038/s43018-024-00821-1