ABSTRACT
Liquid chromatography tandem mass spectrometry (LC-MS/MS) has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody (SHR-1222) in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the pro-posed method was 2.00-500 μg/mL,and this verified method was successfully applied to the tox-icokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods (ratios of drug exposure,0.8-1.0).Notably,two monkeys in the 60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies (ADAs) in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.
ABSTRACT
Aim: We aimed to evaluate the efficacy and safety of apatinib treatment and its impact on the quality of life (QOL) of patients with advanced gastric cancer (GC) who experienced failure with at least two chemotherapeutic regimens. Materials and Methods: All patients received apatinib at a daily dose of 500 mg for 4 weeks per cycle until it was stopped due to disease progression, intolerable toxicity. Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse events 4.0 were used to assess tumor responses and toxicities, respectively. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-STO22 were used to assess the impact on patient's QOL. Results: Twenty-five patients were enrolled, but only 24 were evaluated for therapeutic effects. After apatinib treatment, none of the patients achieved complete response (CR), one achieved partial response (PR), and eight had stable disease (SD), resulting in a disease control rate of 37.5% (CR + PR + SD). Responses to questions regarding abdominal pain, nausea/vomiting, insomnia, constipation, and diarrhea in QLQ-C30 and abdominal pain and reflux in QLQ-STO22 were changed over the course of treatment (P < 0.05). The QOL score was elevated after three treatment cycles, but it was not considered statistically significant (P > 0.05). Conclusion: Results indicated that apatinib was effective in heavily pretreated patients with advanced GC who experienced failure with two or more line chemotherapies. The toxicities were tolerable or could be clinically controlled. Apatinib treatment alleviated some of the clinical symptoms but did not improve QOL significantly.