Anu G. Nair 1, Marlene Biehl 2, Gregor Lotz 3, Nick Corr 1, Iryna Dekhtiarenko 1, Wouter Driessen 1, Miro Julian Eigenmann 1
1 Roche Pharma Research and Early Development, Roche Innovation Center Basel (, Switzerland), 2 Roche Pharma Research and Early Development, Roche Innovation Center Zürich (, Switzerland), 3 Roche Pharma Research and Early Development, Roche Innovation Center Munich (, Germany)
Introduction: BCMA 4-1BBL is a costimulatory molecule designed to enhance T-cell engager efficacy in multiple myeloma (MM). Its bispecific binding profile results in a characteristic bell-shaped exposure-response curve [1]. For its costimulatory effect, BCMA 4-1BBL needs to bind to the BCMA antigen expressed on the membrane of MM cells and crosslink it with T-cells [2]. However, shedding of BCMA creates a soluble sink (sBCMA) in patients that competes for binding and is expected to decrease free drug exposure [3, 4]. The interplay between variable sBCMA levels in patients and the narrow efficacious exposure window of a bell-shaped exposure-response makes clinical dose selection uniquely challenging.
Objectives: We aimed to:
1. Quantify the impact of sBCMA on PK and develop an integrated PK model
2. Characterize the preclinical bell-shaped exposure-response relationship
3. Simulate the expected impact of patient sBCMA variability on free PK in patients and dose-finding in a potential Phase I
Methods: We performed in silico simulations using SPR/FACS-derived binding kinetics to predict the optimal exposure range to be tested for BCMA 4-1BBL. Experimentally, BCMA 4-1BBL was evaluated alongside forimtamig (GPRC5D CD3 T-cell bispecific) [5] across in vitro, ex vivo (patient bone marrow), and in vivo (tumor-bearing mice) models. PK was assessed in hFcRn tg32 mice for human PK projection and together with in vitro potency data formed the bases for a MABEL dose calculation [6]. The impact of sBCMA on apparent in vitro potency was quantified by titrating recombinant sBCMA while assessing the treatment effect of BCMA 4-1BBL. Free and total PK was assessed in vivo in tumor bearing mice allowing assessment of sBCMA impact on free exposure in those mice. A semi-mechanistic PK model was then developed to describe the sBCMA interaction with BCMA 4-1BBL and its impact on free exposures and estimate underlying parameters. After establishing the model based on preclinical data, we sampled from clinical sBCMA baseline level distributions in patients [7] for tailored model simulations. In those simulations we assessed the expected exposure loss at various relevant doses and if at higher doses, around the expected efficacious exposure range, this impact might be mitigated. We further quantified what percent of patients would potentially achieve an optimal exposure within the anticipated bell-shape at given doses to assess if an optimal dose could theoretically be selected for all patients given the wide range of sBCMA levels.
Results: In vitro data confirmed a bell-shaped response peaking at ~10nM, aligning with prior in silico predictions. Ex vivo and in vivo models showed higher variability and the add-on effect of the co-stimulation was overall more difficult to evaluate with potentially higher exposures required. The in vivo PK confirmed that sBCMA acts as a dose-dependent sink, disproportionately reducing free exposure at lower doses. Patient simulations indicate that sBCMA significantly reduces free drug levels, though this may stabilize at higher dose and if tumor burden (and thus sBCMA) declines at later cycles. However, the variability remains substantial even at expected efficacious doses and for patients with high sBCMA levels >90% exposure loss could be expected. Based on our simulations, in the best case, at a dose of 18mg, only slightly less than 80% of the population would have a free exposure within the EC80 window based on the preclinically observed bell-shape; the fraction of patients with optimal exposure is however expected to drop sharply at slightly more suboptimal doses. A substantially higher fraction of patients would fall within a more “lenient” EC50 window, with ~80-95% at doses between 6-76mg. However, given the need to prove an add-on effect on top of an already efficacious T-cell engager, optimal exposure would probably be needed.
Conclusion: Our modeling framework underscores the difficulty of dosing through a soluble sink when constrained by a bell-shaped exposure-response. The model simulations illustrate that achieving optimal exposure across a Phase I population will be tricky. Stratification based on sBCMA level could potentially help, but either way the outlined limitations, together with the difficulty to prove a very clear add-on effect in preclinical ex vivo and in vivo systems, demonstrate that a clinical PKPD assessment of this compound is expected to be highly challenging.
References:
1. Betts A, Haddish-Berhane N, Shah DK, van der Graaf PH, Barletta F, King L, et al. A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART®. AAPS J. 2019;21:66. doi:10.1208/s12248-019-0332-z.
2. Wen T, Bukczynski J, Watts TH. 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J Immunol. 2002;168:4897–906. doi:10.4049/jimmunol.168.10.4897.
3. Girgis S, Wang Lin SX, Pillarisetti K, Verona R, Vieyra D, Casneuf T, et al. Effects of teclistamab and talquetamab on soluble BCMA levels in patients with relapsed/refractory multiple myeloma. Blood Adv. 2023;7:644–8. doi:10.1182/bloodadvances.2022007625.
4. Cai H, Kakiuchi-Kiyota S, Hendricks R, Zhong S, Liu L, Adedeji AO, et al. Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma. AAPS J. 2022;24:100. doi:10.1208/s12248-022-00744-8.
5. Eckmann J, Fauti T, Biehl M, Zabaleta A, Blanco L, Lelios I, et al. Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma. Blood. 2025;145:202–19. doi:10.1182/blood.2024025987.
6. Betts A, Keunecke A, van Steeg TJ, van der Graaf PH, Avery LB, Jones H, Berkhout J. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. MAbs. 2018;10:751–64. doi:10.1080/19420862.2018.1462429.
7. Dekhtiarenko I, Attig J, Helms H-J, Lelios I, Clausen I, Jacob W, et al. P-006 SBCMA has utility for early response monitoring in the blood and is correlated with forimtamig pharmacodynamic activity, clinical response and MRD. Clinical Lymphoma Myeloma and Leukemia. 2023;23:S35-S36. doi:10.1016/S2152-2650(23)01624-5.
Reference: PAGE 34 (2026) Abstr 12266 [www.page-meeting.org/?abstract=12266]
Poster: Drug/Disease Modelling - Oncology