HBsAg and TLR7/8 dual-targeting antibody-drug conjugates induce sustained anti-HBV activity in AAV/HBV mice: a preliminary study.

Hepatitis B virus (HBV) infection is a significant global health concern due to elevated immunosuppressive viral antigen levels, the host immune system's inability to manage HBV, and the liver's immunosuppressive conditions. While immunotherapies utilizing broadly reactive HBV neutralizing antibodies present potential due to their antiviral capabilities and Fc-dependent vaccinal effects, they necessitate prolonged and frequent dosing to achieve optimal therapeutic outcomes. Toll-like receptor 7/8 (TLR7/8) agonists have been demonstrated promise for the cure of chronic hepatitis B, but their systemic use often leads to intense side effects. In this study, we introduced immune-stimulating antibody conjugates which consist of TLR7/8 agonists 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-c]quinolin-4-amine (IMDQ) linked to an anti-hepatitis B surface antigen (HBsAg) antibody 129G1, and designated as 129G1-IMDQ. Our preliminary study highlights that 129G1-IMDQ can prompt robust and sustained anti-HBsAg specific reactions with short-term administration. This underscores the conjugate's potential as an effective strategy for HBsAg clearance and seroconversion, offering a fresh perspective for a practical therapeutic approach in the functional cure of CHB. Highlights: HBV-neutralizing antibody 129G1 was linked with a TLR7/8 agonist small molecule compound IMDQ.Treatment with 129G1-IMDQ has shown significant promise in lowering HBsAg levels in AAV/HBV mice.129G1-IMDQ were eliciting a strong and lasting anti-HBsAg immune response after short-term treatment in AAV/HBV mice.

Unlocking the potential of bispecific ADCs for targeted cancer therapy.

Antibody-drug conjugates (ADCs) are biologically targeted drugs composed of antibodies and cytotoxic drugs connected by linkers. These innovative compounds enable precise drug delivery to tumor cells, minimizing harm to normal tissues and offering excellent prospects for cancer treatment. However, monoclonal antibody-based ADCs still present challenges, especially in terms of balancing efficacy and safety. Bispecific antibodies are alternatives to monoclonal antibodies and exhibit superior internalization and selectivity, producing ADCs with increased safety and therapeutic efficacy. In this review, we present available evidence and future prospects regarding the use of bispecific ADCs for cancer treatment, including a comprehensive overview of bispecific ADCs that are currently in clinical trials. We offer insights into the future development of bispecific ADCs to provide novel strategies for cancer treatment.

FoxO1-modulated macrophage polarization regulates osteogenesis via PPAR-γ signaling.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

A new mechanism of antibody diversity: formation of the natural antibodies containing LAIR1 and LILRB1 extracellular domains.

The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with P. falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system's response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.

Stepping forward: T-cell redirecting bispecific antibodies in cancer therapy.

T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens, thereby engaging with CD3 on the T cell receptor. This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells. These antibodies have emerged as one of the most promising avenues within tumor immunotherapy. However, despite success in treating hematological malignancies, significant advancements in solid tumors have yet to be explored. In this review, we aim to address the critical challenges associated with T cell-redirecting bispecific antibodies and explore novel strategies to overcome these obstacles, with the ultimate goal of expanding the application of this therapy to include solid tumors.

Factors Influencing Readiness for Hospital Discharge among Patients Undergoing Enterostomy: A Descriptive, Cross-sectional Study.

OBJECTIVE: To examine the factors influencing hospital discharge readiness among Chinese patients who have undergone enterostomy. METHODS: In this descriptive, cross-sectional study, researchers recruited patients with colorectal cancer who underwent enterostomy at a tertiary hospital in Guangdong Province, China, via convenience sampling between January 2021 and January 2023. Participants completed the Readiness for Hospital Discharge Scale, Ostomy Self-care Ability Scale, and Stoma-Quality of Life-Chinese Questionnaire (Chinese version) at the time of hospital discharge. Univariate, correlation, and multiple linear regression analyses were performed to explore the impact of self-care ability, quality of life, and other clinicodemographic characteristics on patients' readiness for hospital discharge. RESULTS: Of the 200 questionnaires distributed, 177 (88.5%) were completed and included in the final analysis. The median scores for the factors considered in this study were as follows: Readiness for Hospital Discharge Scale was 148.00 (interquartile range [IQR], 117.50, 164.00), self-care intention of the Ostomy Self-care Ability Scale was 36.00 (IQR, 34.00, 40.00), self-care knowledge of the Ostomy Self-care Ability Scale was 17.00 (IQR, 15.00, 19.00), self-care skill of the Ostomy Self-care Ability Scale was 5.00 (IQR, 3.00, 6.00), and the total score for quality of life was 60.00 (IQR, 49.00, 69.00). Multiple linear regression analysis identified several key factors explaining 48.2% of the variance in global readiness for hospital discharge: global quality of life (ß = .347, P < .001), self-care knowledge (ß = .259, P < .001), leakage during hospitalization (ß = -0.241, P < .001), monthly family income (ß = .148, P = .008), stoma siting before surgery (ß = .130, P = .020), and self-care intention (ß = .127, P = .035). CONCLUSIONS: The readiness for hospital discharge among patients undergoing enterostomy in this study was high. Factors such as quality of life, self-care knowledge, leakage during hospitalization, monthly family income, stoma siting before surgery, and self-care intention after undergoing enterostomy influenced the patients' readiness for hospital discharge. Therefore, future studies should focus on developing interventions to enhance patients' readiness for hospital discharge.

Effect of inactivated vaccine boosters against severe and critical COVID-19 during the Omicron BA.5 wave: A retrospective analysis of hospitalized patients in China.

Few real-world analyses of the ability of vaccines to protect against severe COVID-19 have been published. In this real-world study, we compared the prevalence of severe or critical COVID-19 between patients at our hospital who were not vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or who had been vaccinated partial, full, or booster course with the CoronaVac, containing inactivated virus propagated in Vero cells. Data from electronic health records were retrospectively analyzed for 4090 inpatients with COVID-19 who were treated at West China Hospital, Chengdu between December 6, 2022 and February 14, 2023. Clinicodemographic characteristics and COVID-19 severity were compared among patients who had been vaccinated 0, 1, 2 or more times with inactivated vaccine CoronaVac. To evaluate vaccine effectiveness over time, we plotted Kaplan-Meier curves with the percentage of patients with the outcome of severe or critical COVID-19 from the time of their last vaccine dose according to vaccination status. Ordinal logistic regression was used to assess associations between vaccination status and COVID-19 severity. Cox regression was used to identify risk factors for severe or critical COVID-19. Among the 4090 patients, 171 had been vaccinated partial and 423 twice with the full CoronaVac regimens, while 905 had been vaccinated three times (boosted). The prevalence of severe or critical COVID-19 among patients was 11 percentage points lower among those vaccinated (40%) at least twice than among those unvaccinated (51%) (p＜0.001), while it was 10% points lower among those who had received a booster (41%) than among those unvaccinated (51%) (p＜0.001). Protection against severe or critical COVID-19 due to vaccination was significantly weakened by being older than 65 years, being male, or having diabetes, chronic heart disease, autoimmune disease, or chronic lung disease. Completing a full course of immunization with inactivated vaccine CoronaVac against SARS-CoV-2 can reduce the risk of severe or critical COVID-19 due to the Omicron BA.5 subvariant.

Safety, immunogenicity and protective effectiveness of heterologous boost with a recombinant COVID-19 vaccine (Sf9 cells) in adult recipients of inactivated vaccines.

Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p < 0.001). In the Sf9 cells group, GMTs of neutralizing antibodies against pseudo SARS-CoV-2 viruses (prototype and diverse variants of concern [VOCs]) increased by 22.23-75.93 folds from baseline to day 28 post-booster, while the CoronaVac group showed increases of only 3.29-10.70 folds. Similarly, neutralizing antibodies against live SARS-CoV-2 viruses (prototype and diverse VOCs) increased by 68.18-192.67 folds on day 14 post-booster compared with the baseline level, significantly greater than the CoronaVac group (19.67-37.67 folds). A more robust Th1 cellular response was observed with the Sf9 cells booster on day 14 post-booster (mean IFN-γ+ spot-forming cells per 2 × 105 peripheral blood mononuclear cells: 26.66 vs. 13.59). Protective effectiveness against symptomatic COVID-19 was approximately twice as high in the Sf9 cells group compared to the CoronaVac group (68.18% vs. 36.59%, p = 0.004). Our study findings support the high protective effectiveness of heterologous boosting with the recombinant COVID-19 vaccine (Sf9 cells) against symptomatic COVID-19 of diverse SARS-CoV-2 variants of concern, while causing no apparent safety concerns.

A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration.

Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2 mg kg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10 mg kg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.