Abstract C063: OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies
Authors: Cassier Philippe , Gomez-Roca Carlos , Kotecki Nuria , Massard Christophe , Postel-Vinay Sophie , Morello Aurore , Déramé Mylène , Chevalier Caroline , Cordonnier Laurie , Josse Constant , Comis Silvia , Poirier Nicolas , Robert Marie 
Published: December 2023

Abstract
Background: Anti-PD-1 antibodies have shown significant clinical activity with favorable safety. Bispecific anti-PD-1 antibodies are being developed. OSE279 is a humanized S228P-immunoglobulin (Ig)G4 monoclonal bivalent antibody directed against PD-1 which will be further used as the anti-PD-1 backbone component of a bifunctional checkpoint inhibitor BiCKI® platform.
Methods: We performed preclinical assessments of OSE279 that support development in humans. A FIH study investigating OSE279 is ongoing, evaluating 2 Dose Levels (DLs) of 100 and 300 mg given q3w and 1 DL of 600 mg q6w, according to BOIN design, in subjects with refractory malignancies, with no standard treatments, for which anti-PD1/PDL1 have shown efficacy but are not locally available, or rare tumors with reported activity of anti-PD1, or PDL1 positive tumors. Primary objective is to determine the MTD and/or Recommended Phase 2 Doses (RP2D). Secondary objectives are efficacy, safety, PK and PD profiles. DLT period is 21 days.
Results: Preclinical investigations showed that OSE279 has antagonist activity against PD1, blocking the binding of PD1 ligands (IC50 308 ± 170 ng/mL). OSE279 blocked PDL1-induced SHP1 phosphorylation in a cell-based assay (IC50=14.19 ng/mL) and promoted reactivation of primary T cell effector functions leading to interleukin 2 and Interferon γ secretion in MLR assay. OSE279 showed potent antitumor activity in syngeneic models of colon cancer, hepatocarcinoma and mesothelioma implanted in immunocompetent Human PD1 Knock-in mice, with long-term response and survival. OSE279 showed good affinity to hFcRn receptor predicting good half-life in humans. Simulations showed that trough Receptor Occupancy (RO) would be 94.1±36.9% and 98.3±36.8% at 100 mg and 300 mg, respectively. NOAEL was determined in monkey at 100 mg/kg for 1 month. In the FIH study as of June 2023, 9 subjects were treated, with 8 tumor types. Median age was 60y (range 43-70), 6/9 patients (67%) were female, median number of prior metastatic lines was 2 (range 1-6). 300 mg was declared RP2D for a q3w regimen; a new cohort is exploring 600 mg q6w. One (with HCC) of seven patients in DL2 (300 mg) had a DLT of gr3 hepatitis. Treatment-Related Adverse Events (TRAEs) occurred in 8 patients (88.9%). Serious TRAEs (pneumonitis gr2, hepatitis gr3) occurred in 2 patients (22.2%). A confirmed PR was observed in HCC after one dose of OSE279 300mg. SD was reported in 3 patients. PK profile showed good exposure and dose-proportionality. RO was maintained and within the boundaries of simulation.
Conclusions: OSE279 preclinical data showed comparable efficacy and safety profiles to the EMA/FDA approved anti-PD1 antibodies. In FIH study, OSE279 showed a manageable safety profile with preliminary signs of efficacy in the first 9 patients treated. A RP2D of 300 mg q3w was selected. 600 mg q6w is being evaluated (data available by October 2023). PK and PD profiles were according to modelling. Expansion cohorts are planned. Clinical trial information: NCT 05751798. Research Sponsor: OSE Immunotherapeutics.
Citation Format: Philippe Cassier, Carlos Gomez-Roca, Nuria Kotecki, Christophe Massard, Sophie Postel-Vinay, Aurore Morello, Mylène Déramé, Caroline Chevalier, Laurie Cordonnier, Constant Josse, Silvia Comis, Nicolas Poirier, Marie Robert. OSE279, a PD-1 blocking monoclonal antibody, as future backbone of a bifunctional checkpoint inhibitor platform: Preclinical characterization and early clinical results of a First-In-Human (FIH) study in subjects with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C063.