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
  • 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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