Use of a limited course of low-dose anti-pd-1 antibody in the treatment of hepatitis b

Abstract

The application discloses application of a low-dose anti-PD-1 antibody in a limited course of treatment in treatment of hepatitis B. Anti-PD-1 antibody treatment is carried out on a chronic hepatitis B patient receiving nucleoside analogue or nucleotide analogue treatment, 100 mg is injected intravenously each time, once every three weeks, and the course of treatment is ended after 12 weeks or 24 weeks. The application blocks the combination of the PD-1 receptor highly expressed on the surface of T cells of the CHB patient with a ligand by blocking the CHB patient T cell surface high expression of the PD-1 receptor, thereby reversing the T cell exhaustion state, enhancing the HBV specific T cell immune response, and promoting HBsAg clearance. The application uses a limited course of treatment and a low-dose alpha PD-1 to enhance the HBV specific T cell immune response of the patient and promote the clearance of HBsAg while ensuring good safety. Compared with the traditional 48-week Peg-IFN alpha or several years or even decades of NAs treatment of the CHB patient, the 12-week or 24-week course of alpha PD-1 is shorter and has a smaller economic burden on the patient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and specifically discloses the application of a low-dose anti-PD-1 antibody with a limited course of treatment in the treatment of hepatitis B. Background Technology

[0002] Functional cure (also known as clinical cure) of chronic hepatitis B (CHB) is the treatment goal recommended by current domestic and international guidelines. It is defined as persistent negative HBsAg, HBV DNA below the minimum detection limit, and normal liver biochemical indicators after cessation of treatment. After CHB patients achieve functional cure, the body establishes effective immunological control over HBV, significantly reducing viral rebound and the incidence of end-stage liver disease. However, most patients do not achieve HBsAg clearance after receiving first-line treatment with nucleoside (nucleotide) analogs (NAs) or pegylated interferon-alpha (Peg-IFNα) monotherapy (the overall HBsAg seroconversion rate is less than 10% after one year of treatment).

[0003] CHB patients exhibit deficiencies in both innate and adaptive immune responses against HBV, with T-cell exhaustion being a key reason for the ineffective clearance of HBV. Programmed death receptor 1 (PD-1) is highly expressed on T cells in CHB patients and is an important marker of T-cell exhaustion. Cellular and animal experiments suggest that blocking the PD-1 / PD-L1 pathway can enhance HBV-specific T-cell responses and reverse T-cell exhaustion. Two preliminary international clinical trials have shown that a single injection of an anti-PD-1 antibody (αPD-1, nivolumab) can promote HBsAg reduction. However, the safety of αPD-1 in CHB patients, and its impact on HBsAg levels and immune responses, have not been adequately studied in large-scale patient cohorts. Therefore, αPD-1 is a potential strategy for CHB treatment, but its application in hepatitis B treatment remains in the exploratory stage and has not yet become a standard therapy.

[0004] In view of the above shortcomings, the present invention aims to propose a limited-course, low-dose αPD-1 regimen for the treatment of CHB that has good safety, promotes HBsAg clearance and enhances HBV-specific T-cell immune response. Summary of the Invention

[0005] Based on the above analysis, this invention provides a low-dose anti-PD-1 antibody treatment regimen with good safety and a limited course of treatment for the treatment of chronic hepatitis B, aiming to promote HBsAg clearance and enhance HBV-specific T-cell immune response.

[0006] To achieve the above-mentioned technical effects, the present invention employs the following technical means:

[0007] This invention first discloses the application of a low-dose anti-PD-1 antibody with a limited treatment course in the treatment of hepatitis B, specifically including:

[0008] PD-1 antibody intravenous therapy was administered to patients with chronic hepatitis B who were receiving nucleoside or nucleotide analogue therapy.

[0009] Treatment target: Chronic hepatitis B patients receiving nucleoside analogues or nucleotide analogues.

[0010] Active ingredient: Anti-PD-1 antibody (sintilimab), manufacturer: Innovent Biologics (Suzhou) Co., Ltd., approval number: National Drug Approval Number S20180016.

[0011] Core dosage and regimen: 100 mg, once every three weeks, intravenously, for a course of 12 or 24 weeks.

[0012] Main principle: By blocking the PD-1 receptor highly expressed on the surface of T cells in CHB patients, blocking its binding with ligands, the T cell exhaustion state is reversed, the HBV-specific T cell immune response is enhanced, and HBsAg clearance is promoted.

[0013] The beneficial effects of this invention are as follows:

[0014] 1) Limited course and low dose of αPD-1 can enhance the patient's HBV-specific T cell immune response and promote the clearance of HBsAg while ensuring good safety.

[0015] 2) Compared to the traditional 48-week Peg-IFNα treatment or NAs treatment for several years or even decades for CHB patients, 12-week or 24-week courses of αPD-1 are shorter and less costly for patients. Attached Figure Description

[0016] Figure 1 This is a schematic diagram of the limited-duration (12 weeks or 24 weeks), low-dose αPD-1 treatment regimen of the present invention.

[0017] Figure 2 This is a schematic diagram of the clinical cohort of the clinical studies completed under this invention.

[0018] Figure 3The changes in HBsAg levels in patients after 24 weeks of NA monotherapy or NA combined with αPD-1 therapy are shown. A, B, C, D, and E represent: the average decrease in HBsAg from 0 to 24 weeks after treatment in the NA group and the NA+αPD-1 group (A); the average HBsAg levels in the NA group and the NA+αPD-1 group at each follow-up time point (B); the average decrease in HBsAg from 0 to 12 weeks and from 12 to 24 weeks in the NA group and the NA+αPD-1 group (C); the changes in HBsAg levels and seroconversion status of each patient in the NA+αPD-1 group (D); and the changes in HBsAg levels and seroconversion status of each patient in the NA group (E).

[0019] Figure 4 The study assessed HBV-specific T-cell responses 24 weeks after patients received NA monotherapy or NA combined with αPD-1 therapy. Detailed Implementation

[0020] The present invention will be further illustrated by the following examples, but the present invention is not limited to these specific embodiments.

[0021] Unless otherwise described, the present invention will be carried out using conventional techniques such as cell biology, which are well known to those skilled in the art. Alternatively, it may be carried out according to the instructions provided by the reagent manufacturer. The drugs, raw materials, and reagents provided in this invention are all commercially available.

[0022] The present invention will be further illustrated below with reference to the embodiments:

[0023] Example 1

[0024] The application of a limited-course, low-dose anti-PD-1 antibody in the treatment of hepatitis B, specifically including:

[0025] PD-1 antibody intravenous therapy was administered to patients with chronic hepatitis B who were receiving nucleoside or nucleotide analogue therapy.

[0026] This invention conducts an open-label prospective study. Patient inclusion criteria (meeting all inclusion criteria) are as follows:

[0027] 1. Positive serum HBsAg level and / or serum HBV DNA level for at least 6 months;

[0028] 2. Baseline HBsAg level greater than 100 IU / mL;

[0029] 3. Negative for hepatitis B e antigen (HBeAg);

[0030] 4. Serum HBV DNA level is below 20 IU / mL;

[0031] 5. Prior to enrollment, the patient had received stable treatment with nucleoside analogues or nucleotide analogues (NA) for at least 6 months.

[0032] Exclusion criteria include:

[0033] 1. Age under 18 or over 70;

[0034] 2. Co-infection with other viruses such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), or Treponema pallidum (TP);

[0035] 3. Comorbid cirrhosis or malignant tumors of the liver and other systems;

[0036] 4. During pregnancy or lactation;

[0037] 5. The presence of other serious diseases that may significantly affect immune function;

[0038] 6. History of allergy to related medications;

[0039] 7. Other circumstances deemed unsuitable for participation in this trial by the researchers.

[0040] After screening according to inclusion and exclusion criteria, a total of 121 eligible CHB patients were included and subsequently divided into the NA group (n=62) and the NA+αPD-1 group (n=59). Patients in the nucleoside (nucleotide) analog (NA) group received NA monotherapy for 24 weeks, while patients in the NA+αPD-1 group received nucleoside analogs combined with anti-PD-1 antibodies (the αPD-1 used was sintilimab, at a dose of 100 mg, administered intravenously every 3 weeks) for 24 weeks. Figure 2 ).

[0041] The two groups of patients were well matched in terms of baseline data such as age, sex, and body mass index (BMI), and there was no difference in HBsAg levels between the groups (2.38 vs. 2.37 log10 IU / mL, P = 0.772), indicating that the two groups were comparable (Table 1).

[0042] Table 1. Demographic and clinical baseline characteristics of the subjects

[0043]

[0044] In the NA+αPD-1 group, 8 patients withdrew from the study due to adverse events (mainly thyroid dysfunction and oral mucositis), and 2 patients withdrew for personal reasons, with a total of 49 patients completing the follow-up; all patients in the NA group completed the 24-week follow-up.

[0045] Overall, the incidence of patient-reported adverse events (AEs) and serious adverse events (SAEs) in the NA+αPD-1 group was 88.1% (52 / 59) and 8.5% (5 / 59), respectively (Table 2), both of which were associated with αPD-1. Of all adverse events, 93.6% were mild. Elevated alanine aminotransferase (ALT) (52.5%, 31 / 59) and aspartate aminotransferase (AST) (35.6%, 21 / 59) were the most common adverse events (AEs). Regarding serious adverse events (SAEs), only grade 3 ALT elevation (8.5%, 5 / 59) and grade 3 AST elevation (3.4%, 2 / 59) were observed (Table 2). Notably, all adverse events (AEs) were self-limiting or resolved spontaneously upon discontinuation of the drug and / or symptomatic treatment. This suggests that a 24-week course of αPD-1 treatment is well-safe in patients receiving NA therapy.

[0046] Table 2. Occurrence of adverse events in the NA+αPD-1 group

[0047]

[0048] The data is presented as a quantity (percentage value).

[0049] This study dynamically monitored and compared HBsAg levels in two groups of patients (n=62 in the NA group and n=49 in the NA+αPD-1 group) who completed all 24 weeks of treatment. Results showed that at week 12 of treatment, the mean decrease in HBsAg in the NA+αPD-1 group was -0.706 log10 IU / mL, while in the NA group it was only -0.036 log10 IU / mL, a highly statistically significant difference between the two groups (P < 0.001). By the end of week 24 of treatment, the HBsAg decrease in the NA+αPD-1 group reached -0.720 log10 IU / mL, and in the NA group it was -0.034 log10 IU / mL, with the difference between the groups remaining significant (P < 0.001). Figure 3 A). During the first 12 weeks of treatment, the NA+αPD-1 group showed a sustained and relatively rapid trend of HBsAg decline ( Figure 3 B and Figure 3C), the changes within the group during this period were statistically significant (P < 0.001); however, during weeks 12 to 24, HBsAg levels in this group tended to stabilize, without further significant decrease (P > 0.05). In contrast, the NA group showed a slow decrease in HBsAg levels throughout the 24-week treatment period, with no statistically significant changes (P > 0.05). Another noteworthy finding is the HBsAg clearance rate. In the NA+αPD-1 group, 2 patients (4.1%) achieved HBsAg clearance by week 6; by week 12, the number of clearance cases increased to 3 (6.1%); however, from week 12 to the end of week 24, no new patients achieved HBsAg clearance. Figure 3 D). In contrast, no HBsAg clearance was observed in the NA group throughout the study period. Figure 3 E). The above results suggest that 24 weeks of αPD-1 treatment significantly reduced or even eliminated HBsAg levels in CHB patients, and that shortening the αPD-1 treatment course to 12 weeks may achieve the same effect.

[0050] This invention uses enzyme-linked immunospot (ELISPOT) technology to dynamically monitor the response level of HBV-specific T cells. For example... Figure 4 As shown, at the two key time points of week 12 and week 24, the number of IFN-γ spots on HBV-specific T cells targeting hepatitis B surface antigen (HBsAg), polymerase protein (HBpol), X protein (HBx), and e antigen (HBeAg) all showed a significant upward trend, with statistical results indicating statistically significant differences (P < 0.05). This suggests that αPD-1 treatment significantly enhances the HBV-specific T cell response.

[0051] Furthermore, based on domestic drug purchase prices, the approximate costs of using nucleoside (nucleotide) analogs (NA) for 30 years, 48 ​​weeks of Peg-IFNα, 12 weeks of αPD-1, and 24 weeks of αPD-1 for CHB patients are shown in Table 3. As the table shows, 12-week or 24-week αPD-1 treatment has a shorter course and a lower economic burden on patients.

[0052] Table 3. Drug costs for CHB patients treated with different medications

[0053]

[0054] It should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This way of describing the specification is only for clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

[0055] The detailed descriptions listed above are merely specific descriptions of feasible embodiments of the present invention, and are not intended to limit the scope of protection of the present invention. All equivalent embodiments or modifications made without departing from the spirit of the present invention should be included within the scope of protection of the present invention.

Claims

1. The application of a limited-course, low-dose anti-PD-1 antibody in the treatment of hepatitis B, including: PD-1 antibody intravenous therapy was administered to patients with chronic hepatitis B who were receiving nucleoside or nucleotide analogue therapy.

2. The application according to claim 1, wherein: The intravenous injection dose of the anti-PD-1 antibody is 100 mg per dose, once every three weeks.

3. The application according to claim 1, wherein: The intravenous injection treatment cycle for the anti-PD-1 antibody is 12 weeks or 24 weeks.

4. The application according to claim 1, wherein: The duration of stable treatment with nucleoside or nucleotide analogs is ≥6 months.

5. The application according to claim 1, wherein: The chronic hepatitis B patients must have had positive serum HBsAg and / or serum HBV DNA levels for at least 6 months.

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