A first-in-human phase I study of FS222, a CD137/PD-L1 tetravalent bispecific antibody, in patients with advanced malignancies
Background: Checkpoint Inhibitor (CPI) therapy is standard of care in a range of tumor types but many patients fail to gain long term clinical benefit. Agonist antibodies targeting the T cell costimulatory receptor CD137 (4-1BB) have shown immunestimulatory effects, but hepatotoxicity significantly...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/114671 |
| Acceso en línea: | https://hdl.handle.net/10171/114671 |
| Access Level: | acceso abierto |
| Palabra clave: | Checkpoint Inhibitor (CPI) Tumor CD137 (4-1BB) Hepatotoxicity |
| Sumario: | Background: Checkpoint Inhibitor (CPI) therapy is standard of care in a range of tumor types but many patients fail to gain long term clinical benefit. Agonist antibodies targeting the T cell costimulatory receptor CD137 (4-1BB) have shown immunestimulatory effects, but hepatotoxicity significantly hindered development. FS222, a novel tetravalent bispecific antibody, incorporates two CD137 binding sites in the Fcregion (Fcab) and anti-PD-L1 Fabs in a natural human IgG1 antibody with silenced FcyR activity. FS222’s affinity has been tuned specifically for each target; high affinity to PD-L1 and moderate affinity to CD137. This elicited PD-L1 dependent CD137 activation for a robust immune stimulation in the absence of toxicity, which resulted in strong antitumor activity in syngeneic models (Lakins et al). FS222’s unique format has the potential to deliver strong antitumor clinical activity with good tolerability. Trial Design: This phase 1 trial is a multi-part (A and B) adaptive, dose escalation and expansion study in subjects with advanced malignancies (NCT04740424). FS222 is administered once every 4 weeks intravenously in 28-day treatment cycles. Primary objectives are to determine safety and tolerability and the recommended phase 2 dose (RP2D). Secondary objectives include determining pharmacokinetic (PK) and pharmacodynamic (PD) profiles, immunogenicity, and clinical response. Subjects with specific solid tumor types will be enrolled who have progressed on standard of care therapy. One line of prior CPI therapy is permitted. Part A consists of an accelerated dose titration (ADT) involving single-subject cohorts followed by a classical 3+3 design and dose expansion cohorts in selected tumor types to further characterize safety, PK/ PD and clinical efficacy. Part B consists of tumor-specific efficacy expansion cohorts with Bayesian adaptive statistics. Translational studies will assess peripheral immune cell proliferation and activation, soluble peripheral PD biomarker levels and the correlation of FS222 exposure with selected PD markers of target engagement and response. Other exploratory translational endpoints are also included in the study. Study enrolment began December 2020. |
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