Carretero-Iglesia et al. focused on improving cytotoxicity against multiple myeloma (MM) by designing ISB 2001, a trispecific CD3+ T cell engager co-targeting BCMA and CD38. Compared to controls, ISB 2001 was efficient at killing tumors, even in the presence of soluble competitors, and was effective across a range of BCMA and CD38 expression levels. In addition to a favorable on-target off-tumor safety profile, ISB 2001 resulted in superior cytotoxicity against tumor cells from MM patients, and regressed tumors in xenograft mouse models. A unique model was developed to determine an FIH dose for the ongoing clinical trial.
Contributed by Katherine Turner
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.
Author Info: (1) Ichnos Glenmark Innovation, New York, NY, USA. (2) Ichnos Glenmark Innovation, New York, NY, USA. (3) Ichnos Glenmark Innovation, New York, NY, USA. (4) Ichnos Glenmark Innovat
Author Info: (1) Ichnos Glenmark Innovation, New York, NY, USA. (2) Ichnos Glenmark Innovation, New York, NY, USA. (3) Ichnos Glenmark Innovation, New York, NY, USA. (4) Ichnos Glenmark Innovation, New York, NY, USA. (5) Ichnos Glenmark Innovation, New York, NY, USA. (6) Ichnos Glenmark Innovation, New York, NY, USA. (7) Ichnos Glenmark Innovation, New York, NY, USA. (8) Ichnos Glenmark Innovation, New York, NY, USA. (9) Ichnos Glenmark Innovation, New York, NY, USA. (10) Ichnos Glenmark Innovation, New York, NY, USA. (11) Ichnos Glenmark Innovation, New York, NY, USA. (12) Ichnos Glenmark Innovation, New York, NY, USA. (13) Ichnos Glenmark Innovation, New York, NY, USA. (14) Ichnos Glenmark Innovation, New York, NY, USA. (15) Ichnos Glenmark Innovation, New York, NY, USA. (16) Ichnos Glenmark Innovation, New York, NY, USA. (17) Certara UK Limited, Canterbury Innovation Centre, University Road, Canterbury, United Kingdom. (18) Certara UK Limited, Canterbury Innovation Centre, University Road, Canterbury, United Kingdom. (19) Ichnos Glenmark Innovation, New York, NY, USA. (20) Ichnos Glenmark Innovation, New York, NY, USA. (21) Ichnos Glenmark Innovation, New York, NY, USA. (22) Ichnos Glenmark Innovation, New York, NY, USA. (23) Ichnos Glenmark Innovation, New York, NY, USA. (24) Hematology Service, Department of Oncology and Clinical Pathology Service, Department of Diagnostics, University Hospital Geneva, Geneva, Switzerland. (25) Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of Oxford, Oxford, United Kingdom. (26) Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of Oxford, Oxford, United Kingdom. (27) Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute, University of Oxford, Oxford, United Kingdom. (28) Nantes Universit, Inserm, CNRS, Universit d'Angers, Nantes, France. SIRIC ILIAD, Angers, Nantes, France. (29) Nantes Universit, Inserm, CNRS, Universit d'Angers, Nantes, France. SIRIC ILIAD, Angers, Nantes, France. (30) Nantes Universit, Inserm, CNRS, Universit d'Angers, Nantes, France. SIRIC ILIAD, Angers, Nantes, France. Service d'Hmatologie Clinique, Unit d'Investigation Clinique, CHU, Nantes, France. (31) Nantes Universit, Inserm, CNRS, Universit d'Angers, Nantes, France. SIRIC ILIAD, Angers, Nantes, France. Service d'Hmatologie Clinique, Unit d'Investigation Clinique, CHU, Nantes, France. (32) Ichnos Glenmark Innovation, New York, NY, USA. (33) Ichnos Glenmark Innovation, New York, NY, USA. (34) Ichnos Glenmark Innovation, New York, NY, USA. (35) Ichnos Glenmark Innovation, New York, NY, USA. mario.perro@iginnovate.com. (36) Ichnos Glenmark Innovation, New York, NY, USA.
