Abstract
Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient’s lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.
| Original language | English |
|---|---|
| Pages (from-to) | 260–273 |
| Number of pages | 14 |
| Journal | Blood |
| Volume | 142 |
| Issue number | 3 |
| Early online date | 16 May 2023 |
| DOIs | |
| Publication status | Published - 20 Jul 2023 |
Bibliographical note
Acknowledgments:The authors thank Camille Grandclément, Evangelia Martini, Valentina Labanca, Stefania De Angelis, Isabelle Gruber, Jérémy Berret, Elodie Stainnack, Riccardo Turrini, Estelle Gerossier, Alain Rubod, Min Ma, Tania Melly, Debora Lind, Paul Oster, Estelle Etasse, and Antoine Job for their technical assistance with the ex vivo and in vivo models; Viviane Villard for providing ISB 1342; and Sunitha Gn (Glenmark) for her work on the IP-LC/ MS/MS method. They thank the past Ichnos Sciences SA members, Christelle Ries-Fecourt, Cian Stutz, Amélie Croset, Mégane Pluess, Romain Ollier, and Darko Skegro for their help with developing ISB 1342; Cyrille Touzeau, Nicoletta Lilli, and Sophie Maϊga for access to the patient samples from the MYRACLE (Myeloma Resistance and Clonal Evolution) cohort at CHU Nantes (France), and Cindy Lanvers for her help in collecting patient samples at University Hospital Geneva (Switzerland). The authors are grateful to Sarah Gooding and Mirian Salazar, all patients who donated samples and the HaemBio Biobank, a Medical Research Council and Oxford Biomedical Research Centre funded Biobank, at the MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford, OX3 SDS, for the provision of clinical samples. The authors also thank Jairo A. Matthews and Steven M. Kornblau at the University of Texas MD Anderson Cancer Center, Department of Leukemia, Leukemia Sample Bank for access to samples from patients with T-ALL. The authors also acknowledge the CytocellFlow Cytometry and FACS core facility (SFR Bonamy, BioCore, Inserm UMS 016, CNRS UAR 3556, Nantes, France) for its technical expertise and help, member of the Scientific Interest Group (GIS) Biogenouest and the Labex IGO program supported by the French National Research Agency (n◦ANR-11-LABX-0016-01). Parts of the visual abstract and Figure 3 were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).