Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Serplulimab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands.
The PD-1 receptor occupation of peripheral T cells and interleukin-2 (IL-2) release ability in vitro were studied in the phase 1 trial involving 29 Chinese patients with advanced solid tumour that were injected with single and multiple doses (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg) of serplulimab. The result showed that serplulimab could stably maintain the saturation state of receptor occupation and sustained functional blockage at the dosage from 0.3 mg/kg to 10 mg/kg every 2 weeks interval.
Serplulimab pharmacokinetics has been investigated in a population pharmacokinetic (popPK) analysis that included 1 144 patients with lung cancer (including ES-SCLC) and other solid cancer types from 8 studies. The patients received serplulimab intravenously as monotherapy or combination therapy in the dose range of 0.3 to 10 mg/kg Q2W, 4.5 mg/kg Q3W, 200 mg Q2W, 300 mg Q3W and 400 mg Q4W. The PK was described by a two-compartment model with time-dependent clearance (CL). Inter-individual variability (coefficient of variation, CV) in base CL and central volume of distribution (Vc) was 25.8% and 15.4%. The mean (CV) observed trough concentration at steady state in the ASTRUM-005 trial was 62.5 μg/mL (36.3%).
Serplulimab is administered by intravenous infusion and is therefore immediately and completely bioavailable. Other routes of administration have not been investigated.
Based on a popPK analysis the volume of distribution of serplulimab is approximately 5.73 L.
The metabolic pathway of serplulimab has not been characterised. Serplulimab is expected to be catabolised into small peptides and amino acids by general protein degradation processes.
Based on a popPK analysis, serplulimab clearance (CL) after the first dose is 0.225 L/day. The clearance decreases over time by a maximum of 30.5% (CV 26.3%) with 106 days to reach half of the maximum effect. The half-life at steady state is approximately 24.3 days.
Serplulimab exhibited linear pharmacokinetics over the dose range of 0.3 to 10 mg/kg Q2W (including flat doses of 200 mg Q2W, 300 mg Q3W and 400 mg Q4W) both after single and multiple doses.
No dedicated studies have been performed in special populations. A popPK analysis suggested no difference in the total systemic clearance of serplulimab based on age (23-83 years), race (n=247 Whites and n=895 Asians), and ECOG performance-status score (0 or 1). Serplulimab clearance increased with increasing body weight.
No effect of creatinine or creatinine clearance (CRCL) (Cockcroft-Gault) was found on serplulimab CL based on a popPK analysis in patients with mild (CRCL=60-89 ml/min; n=448), moderate (CRCL=30-59 ml/min; n=102), and severe (CRCL=15-29 ml/min; n=1) renal impairment, and normal renal function (CRCL≥ 90 ml/min, n=591). There are insufficient data in patients with severe renal impairment for dosing recommendations.
No effect of ALT, AST or total bilirubin was found on serplulimab CL based on a popPK analysis in patients with mild (BIL ≤ ULN and AST > ULN or BIL > 1 to 1.5 × ULN and any AST; n=176) and moderate (BIL > 1.5 to 3 × ULN and any AST; n=2) hepatic impairment, and normal (BIL ≤ ULN and AST ≤ ULN; n=956) hepatic function. There are insufficient data in patients with moderate hepatic impairment for dosing recommendations. Serplulimab has not been studied in patients with severe (BIL > 3 × ULN and any AST) hepatic impairment.
In the repeat-dose toxicity study in cynomolgus monkeys dosed for up to 31 weeks, a high incidence of pharmacology-related perivascular mononuclear cell infiltration in the brain choroid plexus was observed at 100 mg/kg. The no observed adverse effect level (NOAEL) in the 31-weeks toxicity study was 50 mg/kg/week, which produced exposure 36 times (calculated by AUC0-t) the exposure in humans at dose of 3 mg/kg every two weeks.
Reproductive toxicity studies have not been performed.
The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.
Two anti-PD-L1 monoclonal antibodies were evaluated in cynomolgus monkeys for reproductive and developmental toxicity and were shown to cause premature delivery, foetal loss and premature neonatal death when administrated to pregnant monkeys.
Therefore, potential risks of administering serplulimab during pregnancy include increased rates of abortion or stillbirth. Based on its mechanism of action, foetal exposure to serplulimab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-related disorders that have been reported in PD-1 knockout mice.
No studies have been performed to assess the genotoxic or carcinogenic potential of serplulimab.
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