2. Academic Validation
  3. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells

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

  • Nat Cancer. 2024 Oct;5(10):1494-1514. doi: 10.1038/s43018-024-00821-1.
Laura Carretero-Iglesia 1,  Olivia J Hall 1,  Jérémy Berret 1,  Daniela Pais 1,  Carole Estoppey 1,  Myriam Chimen 1,  Thierry Monney 1,  Jeremy Loyau 1,  Cyrille Dreyfus 1,  Julie Macoin 1,  Cynthia Perez 1,  Vinu Menon 1,  Isabelle Gruber 1,  Amélie Laurendon 1,  Lydia N Caro 1,  Girish S Gudi 1,  Tomomi Matsuura 2,  Piet H van der Graaf 2,  Stanislas Blein 1,  M Lamine Mbow 1,  Rebecca Croasdale-Wood 1,  Ankita Srivastava 1,  Michael R Dyson 1,  Thomas Matthes 3,  Zeynep Kaya 4,  Claire M Edwards 4,  James R Edwards 4,  Sophie Maiga 5 6,  Catherine Pellat-Deceunynck 5 6,  Cyrille Touzeau 5 6 7,  Philippe Moreau 5 6 7,  Cyril Konto 1,  Adam Drake 1,  Eugene A Zhukovsky 1,  Mario Perro # 8,  Maria Pihlgren # 1
Affiliations

Affiliations

  • 1 Ichnos Glenmark Innovation, New York, NY, USA.
  • 2 Certara UK Limited, Canterbury Innovation Centre, University Road, Canterbury, United Kingdom.
  • 3 Hematology Service, Department of Oncology and Clinical Pathology Service, Department of Diagnostics, University Hospital Geneva, Geneva, Switzerland.
  • 4 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of Oxford, Oxford, United Kingdom.
  • 5 Nantes Université, Inserm, CNRS, Université d'Angers, Nantes, France.
  • 6 SIRIC ILIAD, Angers, Nantes, France.
  • 7 Service d'Hématologie Clinique, Unité d'Investigation Clinique, CHU, Nantes, France.
  • 8 Ichnos Glenmark Innovation, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 39261676 DOI: 10.1038/s43018-024-00821-1
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.

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