Abstract 1238: ISB 2001, a BCMA and CD38 dual targeting T cell engager, demonstrates superior cytotoxicity relative to teclistamab in the samples of patient relapsing from CD38 and BCMA targeted immunotherapies
Authors: Carretero-Iglesia Laura , Pihlgren Maria , Berret Jeremy , Drake Adam , Pais Daniela , Dreyfus Cyrille , Menon Vinu , Matthes Thomas , Edwards Claire , Edwards James , Pellat-Deceunynck Catherine , Moreau Philippe , Touzeau Cyrille , Matsuura Tomomi , van der Graaf Piet , Pacaud Lida , Konto Cyril , Zhukovsky Eugene , Perro Mario 
Published: March 2024

Abstract
Immune therapies targeting single tumor associated antigens (TAA) demonstrated efficacy against multiple myeloma (MM). However, durable responses are still limited1 potentially due to expansion of clones with low target expression2 We have previously demonstrated that simultaneous targeting of BCMA and CD38 on MM tumor cells with heterogenous expression of these antigens using dual targeting ISB 2001, enables superior killing relative to mono-targeting T cell engagers (TCE) 3. Here we present a further characterization of a dual targeting TCE utilizing bone marrow aspirates from multiple myeloma patients. In relapsed/refractory (r/r) patients, which received CD38 targeted therapy, daratumumab cytotoxicity was substantially reduced due to low CD38 expression. Teclistamab is considered the next line of treatment in such patients. However, ISB 2001 consistently demonstrated increased cytotoxicity compared to teclistamab in both newly diagnosed patient and r/r patient samples. Remarkably, ISB 2001 also induced stronger cytotoxic response in one patient relapsing after BCMA targeted therapy, suggesting that the dual targeting ISB 2001 TCE can overcome the escape mechanisms. ISB 2001 was also compared to the combination of teclistamab and daratumumab in cytotoxic assay using healthy donors. ISB 2001 shows superiority to both teclistamab and daratumumab as single agents, as well as when they were used in combination. Additionally, ISB 2001 was compared against a combination of daratumumab and teclistamab in a humanized mouse model of multiple myeloma with a low expression of both CD38 and BCMA, mimicking potential tumor escaping clones. ISB 2001 induced complete eradication of the tumors in almost all animals, whereas the combination only showed partial tumor protection, underscoring that dual targeting by a TCE is superior to two therapeutic agents individually targeting the same antigens. Based on the promising preclinical in vitro, ex vivo and in vivo data, we have advanced ISB 2001 into clinical studies. For calculating the first-in-human (FIH) dose, we have developed a quantitative systems pharmacology (QSP) model. The calculated FIH dose was 50-100 fold higher than that generated by a traditional minimum anticipated biological effect level calculation. Therefore, using this approach will substantially reduce patient exposure to sub-efficacious doses of ISB 2001. This plan was accepted by the HREC in Australia and the FDA in the US to initiate a Phase 1 FIH study of ISB 2001 for the treatment of relapsed/refractory multiple myeloma (NCT05862012)4.
1. Munshi, N. C. et al. 384, 705-716 (2021).
2. Nijhof, I. S. et al. Blood 128, 12 (2016).
3. (https://doi.org/10.1182/blood-2022-159353)
4. Abstract# 3396, ASH 2023, Hanlon Sia at al.
Citation Format: Laura Carretero-Iglesia, Maria Pihlgren, Jeremy Berret, Adam Drake, Daniela Pais, Cyrille Dreyfus, Vinu Menon, Thomas Matthes, Claire Edwards, James Edwards, Catherine Pellat-Deceunynck, Philippe Moreau, Cyrille Touzeau, Tomomi Matsuura, Piet van der Graaf, Lida Pacaud, Cyril Konto, Eugene Zhukovsky, Mario Perro. ISB 2001, a BCMA and CD38 dual targeting T cell engager, demonstrates superior cytotoxicity relative to teclistamab in the samples of patient relapsing from CD38 and BCMA targeted immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1238.