Abstract CT147: Pharmacokinetics (PK) and pharmacodynamics (PD) of ISB 2001, a novel BCMAxCD38xCD3 trispecific antibody from the first-in-human (FIH) phase 1 study in relapsed/refractory multiple myeloma patients

Abstract Background: ISB 2001 is a trispecific T-cell engager antibody that targets BCMA and CD38 on myeloma cells, with binder affinity tuning and distal positioning of the CD38 vs CD3 binders in order to drive potent tumor killing while minimizing CD38-related off-tumor adverse events. We report here PK and PD results from the ongoing FIH Phase 1 study of ISB 2001. Methods: ISB 2001 is administered weekly by subcutaneous (SC) injection, with step-up doses on days (D) 1 and 4 followed by full target dose on D8 onwards. PK and PD profiles were monitored by assessing ISB 2001 serum concentrations, T-cell activation markers and serum concentrations of soluble biomarkers at multiple post-treatment time points. Potential longer-term translational effects were also evaluated in samples collected monthly during treatment. Results: As of 10 January 2025, 21 patients received ISB 2001 across 7 dose levels between 5-1200 μg/kg. ORR across the effective dose levels (50-1200 µg/kg) was 89.5% (n=19), and 78% in the 9 patients treated with prior T-cell-directed therapy. Serum soluble BCMA levels and circulating B-cell counts were reduced rapidly within the first 2 treatment cycles, consistent with the short median time to response after the first 28-day cycle. PK data up to 1200 µg/kg showed a dose proportional increase in serum exposures with a tentative half-life > 10 days, supporting the potential for less-frequent dosing. Transient increases in cell surface expression of multiple T-cell activation markers were observed on both CD8+ and CD4+ T-cells, including Ki-67, PD-1, CD25, HLA-DR, CD137, TIM-3 and LAG-3. Transient increases in cytokine levels (e.g. IL-6, IL-8, IL-10) were also observed in some patients treated with ISB 2001; concomitantly, patients experienced only Grade 1 (n=14) or 2 (n=2) CRS primarily following the first (n=13) or second (n=7) doses of ISB 2001, with no ICANS, as well as no dose-limiting toxicity, Grade 5 AE or AE leading to discontinuation across all dose levels up to 1200 μg/kg. Conclusion: ISB 2001, a novel BCMAxCD38xCD3 trispecific antibody demonstrated dose proportional PK and a high ORR across a range of dose levels in patients with heavily pre-treated RRMM, including patients previously treated with T-cell-directed therapies. Biomarker observations to date support the tumor-directed specificity of the mechanism of action and are consistent with the mild to moderate immune-related toxicity in clinic. Dose-escalation continues with no DLT observed thus far (NCT05862012). Citation Format: Andrew Garton, Vinu Menon, Hang Quach, Amit Khot, Brad Augustson, Hanlon Sia, David Levitz, Eben Lichtman, Michaela Liedtke, Camille Martinet, Beata Holkova, Lida Pacaud, Sunitha GN, Maria Pihlgren, Mario Perro, Cyril Konto. Pharmacokinetics (PK) and pharmacodynamics (PD) of ISB 2001, a novel BCMAxCD38xCD3 trispecific antibody from the first-in-human (FIH) phase 1 study in relapsed/refractory multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT147.