Utilization analysis of monoclonal antibodies in China under the background of tiered healthcare delivery system / 中国药房

OBJECT IVE To deeply unders tand the utilization of monoclonal antibody drugs in different levels of medical institutions in China ，so as to provide an empirical basis for further promoting tiered healthcare delivery system. METHODS The basic informations of listed monoclonal antibody drugs in China as of May 2021 were collected through the official websites of government agencies such as National Medical Products Administration and National Healthcare Security Administration ，so as to understand the overall development status of monoclonal antibody drugs in China. The clinical utilization data of monoclonal antibody drugs in all categories of antitumor drugs and immune modulators were collected through “chemical drug terminal of Chinese public medical institutions ”database of Metnet ；the clinical application of monoclonal antibody drugs in medical institutions at different levels was analyzed. RESULTS As of May 2021，there were 53 monoclonal antibody drugs had been approved for listing in China ，including 31 imported monoclonal antibody drugs and 22 domestic monoclonal antibody drugs. From 2015 to 2019，the amount and quantity of monoclonal antibody drugs used in urban medical institutions were the highest among the three levels of medical institutions （both accounted for more than 95％ for five consecutive years ），but the growth rate of drug use in county-level medical institutions was the fastest. In 2019，the cumulative proportion of DDDs and drug amount of the top 10 monoclonal antibody drugs ranked in DDDs were the highest among county-level medical institutions ，being 97.09％ and 94.16％ respectively. From the change trend of DDDc of monoclonal antibody drugs from 2015 to 2019，DDDc of cetuximab decreased the most （70.32％），followed by trastuzumab （67.29％） and bevacizumab（62.89％）. From 2015 to 2019，the number of monoclonal antibody drugs with B/A value of no less than 1 ranked the top 10 of the annual cost were 6，6，6，7 and 5， respectively. CONCLUSIONS In China ，the overall approval and listing speed of monoclonal antibody drugs has accelerated，their quantity has increased rapidly ，and the accessibility is also improved. Among them ，the quantity of monoclonal antibody drugs has increased the fastest in county-level medical institutions ，and they are mainly medical insurance drugs ，and the effect of tiered healthcare delivery system has gradually appeared.

Development of Label-Free Immunoassays as Novel Solutions for the Measurement of Monoclonal Antibody Drugs and Antidrug Antibodies.

BACKGROUND: Immunoassays based on label-free technologies (label-free immunoassay [LFIA]) offer an innovative approach to clinical diagnostics and demonstrate great promise for therapeutic drug monitoring (TDM) of monoclonal antibody (mAb) drugs. An LFIA measures immunocomplex formation in real time and allows for quantification on initial binding rate, which facilitates fast measurement within a few minutes. METHODS: Based on thin-film interferometry (TFI) technology, open-access LFIAs were developed for the quantification of the mAb drugs adalimumab (ADL) and infliximab (IFX) and for the detection of the antidrug antibodies (ADAs) to the mAb drugs (ADL-ADAs and IFX-ADAs). RESULTS: The LFIAs for active mAb drugs (ADL and IFX) and for ADAs (ADL-ADAs and IFX-ADAs) were validated. The analytical measurement range (AMR) for both ADL and IFX was from 2 to 100 µg/mL. The AMR for ADL-ADAs was from 5 to 100 µg/mL and for IFX-ADAs was 10 to 100 µg/mL. In the comparison of LFIAs and reporter gene assays, the correlation coefficient was 0.972 for the quantification of ADL and 0.940 for the quantification of IFX. The concordance rate was 90% for the detection of ADL-ADAs and 76% for the detection of IFX-ADAs. CONCLUSIONS: The LFIAs for active mAb drugs and ADAs were appropriate for the TDM of ADL and IFX. The TFI technology has unique advantages compared with other technologies used for the measurement of mAb drugs. Label-free technologies, especially those allowing for open-access LFIAs, have great potential for clinical diagnostics.

In vitro human helper T-cell assay to screen antibody drug candidates for immunogenicity.

Monoclonal antibody (mAb) drugs offer a number of valuable treatments. Many newly developed mAb drugs include artificial modification of amino acid sequences from human origin, which may cause higher immunogenicity to induce anti-drug antibodies (ADA). If the immunogenicity of a new candidate can be understood in the nonclinical phase, clinical studies will be safer and the success rate of development improved. Empirically, in vitro immunogenicity assays with human cells have proved to be sufficiently sensitive to nonhuman proteins, but not to human/humanized mAb. To detect the weaker immunogenicity of human-based mAb, a more sensitive biomarker for in vitro assays is needed. The in vitro study here developed a proliferation assay (TH cell assay) using flow cytometry analysis that can detect a slight increase in proliferating TH cells. Samples from 218 donors treated with a low-immunogenic drug (etanercept) were measured to determine a positive threshold level. With this threshold, positive donor percentages among PBMC after treatment with higher-immunogenicity mAb drugs were noted, that is, 39.5% with humanized anti-human A33 antibody (hA33), 27.3% with abciximab, 25.9% with adalimumab, and 14.8% with infliximab. Biotherapeutics with low immunogenicity yielded values of 0% for basiliximab and 3.7% for etanercept. These data showed a good comparability with previously reported incidences of clinical ADA with the evaluated drugs. Calculations based on the data here showed that a TH cell assay with 40 donors could provide statistically significant differences when comparing low- (etanercept) versus highly immunogenic mAb (except for infliximab). Based on the outcomes here, for screening purposes, a practical cutoff point of 3/20 positives with 20 donors was proposed to alert immunogenicity of mAb drug candidates.

Importance of cynomolgus monkeys in development of monoclonal antibody drugs.

Animal species used in the preclinical studies for development of monoclonal antibody (mAb) drugs are surveyed in this review. Relevant animal species for preclinical studies of mAb candidates are those express desired epitope of mAb candidates. Cynomolgus monkeys cross-react with mAb drugs much higher than other animal species commonly used in preclinical studies such as absorption, distribution, metabolism and excretion (ADME), efficacy, and toxicity studies, for development of new drugs. Moreover, plasma exposure of the mAb drugs in humans is predicted well from the exposure in the monkeys, and the placental transfer of immunoglobulin G (IgG, all the mAb drugs contain IgG) from mother to fetus is similar between humans and the monkeys from a viewpoint of time course and plasma level of IgG transferred. These observed findings indicate that the monkeys are the most suitable animal species used in the ADME and toxicity studies for development of new mAb drugs.