Magnesium-based bioabsorbable cardiovascular stents have been developed to overcome limitations of permanent metallic stents, such as late stent thrombosis. During stent degradation, endothelial and smooth muscle cells will be exposed to locally high magnesium concentrations with yet unknown physiological consequences. Here, we investigated the effects of elevated magnesium concentrations on human coronary artery endothelial and smooth muscle cell (HCAEC, HCASMC) growth and gene expression. In the course of 24 h after incubation with magnesium chloride solutions (1 or 10 mM) intracellular magnesium level in HCASMC raised from 0.55 ± 0.25 mM (1 mM) to 1.38 ± 0.95 mM (10 mM), while no increase was detected in HCAEC. Accordingly, a DNA microarray-based study identified 69 magnesium regulated transcripts in HCAEC, but 2172 magnesium regulated transcripts in HCASMC. Notably, a significant regulation of various growth factors and extracellular matrix components was observed. In contrast, viability and proliferation of HCAEC were increased at concentrations of up to 25 mM magnesium chloride, while in HCASMC viability and proliferation appeared to be unaffected. Taken together, our data indicate that magnesium halts smooth muscle cell proliferation and stimulates endothelial cell proliferation, which might translate into a beneficial effect in the setting of stent associated vascular injury.

Monoclonal antibodies that block the interaction between programmed cell death 1 (PD-1) and its ligand (PD-L1) have revolutionized cancer immunotherapy. However, immunogenic responses to these new therapies—such as the development of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)—may represent a significant challenge to both efficacy and safety in some patients. Dostarlimab (TSR-042) is an approved, humanized, anti-PD-1 monoclonal antibody that has shown efficacy in multiple solid tumor types. Here, we report the results of an immunogenicity analysis of dostarlimab monotherapy in patients enrolled in the GARNET trial, a multicenter, open-label, single-arm phase 1 study. Overall, 477 of 478 patients (99.8%) were included in the analysis of dostarlimab antibody prevalence, and 349 out of 478 enrolled patients (73.0%) were evaluable for treatment-emergent antibodies to dostarlimab. The incidence of treatment-emergent ADAs was 2.5% at the recommended therapeutic dose (500 mg Q3W for the first 4 doses, 1000 mg Q6W until discontinuation), which is comparable to other anti-PD-(L)1 drugs. NAbs were detected in only 1.3% of patients. In the small percentage of patients who developed ADAs, there was no evidence of altered efficacy or safety of dostarlimab at the recommended dosing regimen. These findings demonstrated that treatment with dostarlimab was associated with a low risk of eliciting clinically meaningful ADAs over the course of this study, and dostarlimab is already approved by health authorities.

Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD. Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported. Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Fourteen subjects completed the study. Median age was 42 years (range 22 - 52 years); median body weight was 73.6 kg (range 63.7 - 89.3 kg). Through the pre-specified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. During the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were headache, myalgia, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean C max following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated predose PLA formation was 33 - 39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained through at least 12 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects. Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed through at least 12 weeks, consistent with prior observations. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs. Funding: This study was supported by Global Blood Therapeutics. Disclosures Mayer: Global Blood Therapeutics: Consultancy. Redfern: Linear Clinical Research: Current Employment; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board; Eisai: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Geng: Global Blood Therapeutics: Current Employment. Shi: Global Blood Therapeutics: Current Employment. van Zutphen-van Geffen: Global Blood Therapeutics: Consultancy. Kuan: Global Blood Therapeutics: Consultancy. Koeck: Global Blood Therapeutics: Consultancy. Kastrissios: Global Blood Therapeutics: Consultancy. Patel: Global Blood Therapeutics: Consultancy. Davis: Global Blood Therapeutics: Current Employment. Yue: Global Blood Therapeutics: Current Employment.