Integrated Preclinical Data Analysis of ISB 2001 Enables Optimal Starting Dose Selection for a First-in-Class Trispecific T Cell Engager Phase1 Study in Multiple Myeloma
Authors: Drake Adam , Pihlgren Maria , Menon Vinu , Pais Daniela , Carretero-Iglesia Laura , Berret Jeremy , Hall Olivia , Macoin Julie , Gruber Isabelle , Stainnack Elodie , Estoppey Carole , Dreyfus Cyrille , Gudi Girish , Matsuura Tomomi , van der Graft Piet H , Dyson Michael , Konto Cyril , Pacaud Lida , Srivastava Ankita , Zhukovsky Eugene , Perro Mario 
Published: December 2023

Despite significant clinical benefit achieved by targeted immunotherapies in recent years, durable responses are still limited in multiple myeloma (MM) 1,2 potentially due to expansion of clones with low target expression 3,4,5. We have previously reported ISB 2001 as a first in class trispecific T cell engager (TCE) targeting BCMA and CD38 with a superior potency to a single Tumor Associated Antigen TCE 6,7.
TCEs are often not fully cross reactive with preclinical species for conducting GLP toxicology. For TCEs, a MABEL approach is often used to derive a starting dose 9, generally requiring multiple dose escalations with low probability of patient benefit before an efficacious dose is reached. As ISB 2001 lacks cynomolgus cross reactivity, we could have used a MABEL approach to derive the starting dose. Instead, we generated datasets employing in vitro and in vivo models for ISB 2001 and teclistamab (possessing a similar mode of action). A quantitative systems pharmacology (QSP) model 8 incorporating in vitro and in vivo data was developed and used to predict clinically efficacious doses for both molecules. The QSP model demonstrated that inclusion of in vivo data was key to the best prediction of actual clinical efficacy for teclistamab. Based on this benchmarking, the ISB 2001 efficacious dose range and minimal pharmacologically active dose (MPAD) were derived. Further refinement of the starting dose was performed by introducing step-up dose administration to mitigate the risk of cytokine release syndrome and to reduce the concentration of the first administration of ISB 2001 below the threshold of cytokine release in vitro. This strategy led to the first full dose, which was approximately two-fold lower than the MPAD but 60-fold greater than the MABEL-based starting dose, and therefore significantly reduced patient exposure to sub-therapeutic doses. This approach for the selection of the starting dose for the First-in-Human clinical study was accepted by the U.S. FDA and the Human Research Ethics Committee in Australia. The utility of QSP modelling in the development of trispecific TCEs has been demonstrated before 10,11. However, to our knowledge this is the first time that a starting dose in clinical studies of a trispecific TCE, lacking species cross-reactivity and therefore a GLP toxicology preclinical package, has been derived based on integrated preclinical data analysis utilizing a QSP model.
Clinical evaluation of ISB 2001 is ongoing in a phase I dose escalation and dose expansion study in subjects with relapsed/refractory MM (NCT05862012).
References
1. N. C. Munshi et al., N Engl J Med. 384, 705-716 (2021).
2. P. Moreau et al., N Engl J Med. 387, 495-505 (2022).
3. L. G. Rodríguez-Lobato, et al., Hemato. 2, 1-42 (2020).
4.I. S. Nijhof et al., Blood. 128, 959-970 (2016).
5. A. D. Cohen et al., J Clin Invest. 129, 2210-2221 (2019).
6. M. Pihlgren et al., Blood. 140, 858-859 (2022).
7. M. Pihlgren et al., Cancer Res.83, 2970-2970 (2023).
8. A. Betts et al., AAPS J.21, 66 (2019).
9. H. Saber, et al., Regulatory Toxicology and Pharmacology. 90, 144-152 (2017).
10. K. Ball, et al. mAbs. 15, 2181016 (2023).
11. R. E. Abrams et al., Sci. Reports. 12, 10976 (2022).