The poster was presented at ACoP 2026
Authors: Jingqi Q. X. Gong (1), Tatiana Karelina (2), Dmitry Shchelokov (2), Polina Maliukova (2), Olga Ivanova (2), Maria Myshkina (2), Oleg Demin Jr (2), John Clements (1), Stefan Zajic (1), Murad Melhem (3)
Affiliation: (1) GSK, Collegeville, PA, USA, (2) InSysBio, (3) GSK, Waltham, MA, USA
Objectives: To develop and validate a quantitative systems pharmacology (QSP) model for prostate-specific membrane antigen (PSMAxCD3) T-cell engagers (TCEs) in metastatic castrate-resistant prostate cancer (mCRPC) capable of (1) mechanistically linking TCE exposure and target engagement to downstream tumor effects and immune responses, (2) informing and predicting biomarkers related to clinical efficacy (prostate-specific antigen [PSA] dynamics), and safety (key cytokine time courses) across dosing regimens. The cytokine dynamics then input into probabilistic estimates of cytokine release syndrome (CRS) incidence and severity, and the QSP model can ultimately be used to support efficient first-in-human (FIH) design.
Methods: The mechanistic QSP framework integrates tumor and immune cell kinetics; TCE exposure; T-cell activation, proliferation, and dynamics in plasma and tumor in response to TCE treatment; and downstream cytokine release. The model was calibrated and validated using in vitro and clinical data from two PSMAxCD3 TCEs (acapatamab [1-2] and pasotuxizumab [3-4]). Cytokine-based CRS prediction was implemented adapting a method from Zhang et al. [5], using piecewise probability functions. These functions compare the increase of IL-6 and IFN-γ from baseline to that of reference levels reported from CAR-T therapies corresponding to CRS grades and compute individual and cohort- level probabilities for Grade 0, Grade 1–2 (Gr1–2), and Grade 3 or higher (Gr3+) CRS. A dexamethasone PK/PD sub-model describing corticosteroid effects on CD3+ T-cell migration, proliferation, activation, and cytokine release was also incorporated to capture the impact of dexamethasone on CRS incidence and severity.
Results: The QSP model captured acapatamab and pasotuxizumab PK, target engagement, and the downstream pharmacology of cytokine release and tumor cell killing. A virtual population (Vpop) was constructed incorporating the baseline tumor burden and PSMA expression from acapatamab Ph1 study population [2]. The Vpop simulations reproduced PSA responses, cytokine dynamics and CRS incidence/severity across acapatamab dose cohorts following calibration. Model validation was further performed using pasotuxizumab Ph1 data [4], where predicted PSA50 response, maximal PSA reduction and the CRS incidence were in line with the clinical outcomes reported. The cytokine-based CRS risk predictions provided cohort-level estimates of Gr3+ and Gr1–2 CRS probabilities. Simulations exploring various dosing strategies and dexamethasone premedication quantified trade-offs between PSA response and CRS risk. This QSP framework may be used to inform starting dose for PSMAxCD3 TCE FIH studies.
Conclusions: A QSP model of PSMAxCD3 TCE for the treatment of mCRPC was developed and validated using publicly available data. The model translates various dosing regimens to TCE exposure and circulating efficacy-related biomarker response, along with predicted clinical CRS event grades and incidences. The novel cytokine-based CRS risk prediction improves the clinical relevance of QSP simulations for risk–benefit evaluation and supports starting dose selection and clinical trial design for T-cell engaging therapies.
Citations: [1] Tran BL, Horvath T, Dorff M, et al. 609O Results from a phase I study of AMG 160, a half-life extended (HLE), PSMA-targeted, bispecific T-cell engager (BiTE®) immune therapy for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2020;31(suppl 4, abstr):S507. https://www.annalsofoncology.org/article/S0923-7534(20)40865-8/fulltext
[2] Dorff T, Horvath LG, Autio K, et al. A phase I study of acapatamab, a half-life extended, PSMA-targeting bispecific T-cell engager for metastatic castration-resistant prostate cancer. Clin Cancer Res. 2024;30(8):1488-1500. doi: 10.1158/1078-0432.CCR-23-2978.
[3] Friedrich M , Raum T, Lutterbuese R, et al. Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-bispecific BiTE antibody cross-reactive with non-human primate antigens. Mol Cancer Ther. 2012;11(12):2664-2673. doi: 10.1158/1535-7163.MCT-12-0042.
[4] Hummel HD, Kufer P, Grüllich C, et al. Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings. Immunotherapy. 2021;13(2):125-141. doi: 10.2217/imt-2020-0256.
[5] Zhang Z, Liu L, Ma C, Chen W. A computational model of cytokine release syndrome during CAR T-cell therapy. Adv Ther (Weinh). 2022;5(10):2200130. doi: 10.1002/adtp.202200130.
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