Formulation Development Of High Concentration PD-1 Monoclonal Antibody For Subcutaneous Injection

Marketed monoclonal antibody drugs targeting PD-1,which administration method was intravenous infusion.In order to address unmet clinical demands and provide doctors and patients with more flexibility and better compliance,to develop high-concentration PD-1 mab formulation for subcutaneous.Through the study of stabilizers(First round of formulation development),buffer(Second round of formulation development)and surfactant content(Third round of formulation development)and stability study,the high concentration formulation with low viscosity and good stability was screened.The formulation pH was 5.5 to 6.5,and the concentration of PD-1 mab was 160～200 mg/mL,consisted of 10～30 mmol/L histidine and histidine hydrochloride,120～180 mmol/L arginine hydrochloride and 0.02～0.08%Polysorbate 80.The results showed that the quality and stability of newely-developed subcutaneous drug formulation with high-concentration and original intravenous drug formulation with low-concentration were highly comparable.The subcutaneous drug formulation had a good prospect of productivity and development.In addition,the pharmacokinetic study with a single dose of 4 mg/kg in cynomolgus monkeys showed that subcutaneous administration of the newly-developed high-concentration formulation had high bioavailability,reaching 95.9%.In vivo efficacy tests of preclinical showed that PD-1 mab demonstrated significant tumor suppressive effect in mouse models by subcutaneous injection.At the dose level of 0.3 mg/kg,the tumor suppressive volume of PD-1 mAb by subcutaneous injection was equivalent to that by intravenous injection,which TGITV,was 56.3%and 63.3%respectively showing no significant difference,Under the condition of 0.3～3 mg/kg subcutaneous injection,the TGITV was 56.3%,60.8%and 67.4%respectively showing no obvious dose-dependence,which indicating significant tumor suppressive volume effect;At the dose level of 0.3 mg/kg,the tumor suppressive weight of PD-1 mAb by subcutaneous injection was equivalent to that by intravenous injection,which TGITV,was 53.7%and 63.0%respectively showing no significant difference,The TGITW of subcutaneous administration at 0.3 mg/kg,1 mg/kg and 3 mg/kg were 53.7%,53.4%and 61.1%,respectively indicating significant tumor suppressive weight effect,in addition,PD-1 mAb is well tolerated subcutaneously in animals.Pharmacokinetic and pharmacodynamic studies of subcutaneous and intravenous administration are highly comparable.On the basis of this study,PD-1 mAb subcutaneous injection has been approved for clinical trials by the CDE,these study data can support the clinical development and evaluation of high-concentration subcutaneous formulations of PD-1 mAb.