Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults.

INTRODUCTION: Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful "cytokine and chemokine storm" in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). METHODS: Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. RESULTS: The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration-time curve from time zero to 480 h (AUC0-480h), that from time zero to infinity (AUCinf), and peak plasma concentration ©max) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. CONCLUSION: The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. TRIAL REGISTRATION NUMBER: CTR20200429.

Metabolic Syndrome Predicts Response to Neoadjuvant Chemotherapy in Breast Cancer.

Purpose: This research investigated the predictive role of metabolic syndrome (MetS) in breast cancer neoadjuvant chemotherapy (BCNACT) response. Methods: One hundred fifty primary breast cancer (BC) patients who underwent neoadjuvant chemotherapy (NACT) were included retrospectively. MetS, MetS components [waist circumference (WC), fasting blood glucose (FBG), blood pressure, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C)], serum lipid, and other MetS-related laboratory indicators within two weeks before BCNACT were evaluated. Univariate, multivariate, and subgroup analyses were performed to determine the predictors of BCNACT pathologic complete response (pCR), clinical response, and pathologic response. The effectiveness of the model was evaluated via receiver operating characteristic curve (ROC) and calibration curve. External validation was performed through 135 patients. Results: Univariate analysis revealed that MetS before BCNACT predicted poor BCNACT response (pCR, P = 0.003; clinical response, P = 0.033; pathologic response, P < 0.001). Multivariate analysis confirmed that MetS before BCNACT predicted lower pCR rate (P = 0.041). Subgroup analysis showed that this relationship was significant in estrogen receptor (ER) (-) (RR = 0.266; 95% CI, 0.074-0.954), human epidermal growth factor 2 (HER2) (-) (RR = 0.833; 95% CI, 0.740-0.939) and TNBC (RR = 0.833; 95% CI, 0.636-0.995). Multivariate analysis of external validation confirmed that pretreatment MetS was associated with a lower pCR rate (P = 0.003), and subgroup analysis also confirmed that this relationship had significant statistical differences in ER (-), HER2 (-), and TNBC subgroups. Conclusions: MetS before BCNACT predicted a lower pCR rate. Intervention on MetS status, especially in ER (-), HER2 (-), and TNBC subgroups, is expected to improve the response rate of BCNACT further.

Clinical outcomes of patients with hepatic insufficiency undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is currently a common treatment in high-risk aortic stenosis patients, but the impact of hepatic insufficiency on prognosis after TAVI is debatable and whether TAVI is superior to surgical aortic valve replacement (SAVR) in patients with hepatic insufficiency is uncertain. OBJECTIVE: To investigate the effect of abnormal liver function on the outcome and safety after TAVI and whether TAVI is superior to SAVR in patients with hepatic insufficiency. METHODS: PubMed, Embase, the Cochrane Library and Web of Science were systematically searched from inception up to 26 November 2021. Studies were eligible if mortality and complications after TAVI in patients with and without hepatic insufficiency, or mortality and complications for TAVI versus SAVR in patients with hepatic insufficiency were reported. The Newcastle-Ottawa scale (NOS) was used to evaluate the quality of each study. This meta-analysis was registered with PROSPERO (CRD42021253423) and was carried out by using RevMan 5.3 and Stata 14.0. RESULTS: This meta-analysis of 21 studies assessed a total of 222,694 patients. Hepatic insufficiency was associated with higher short-term (in-hospital or 30-day) mortality [OR = 1.62, 95% CI (1.18 to 2.21), P = 0.003] and 1-2 years mortality [HR = 1.64, 95% CI (1.42 to 1.89), P < 0.00001] after TAVI. Between TAVI and SAVR in patients with hepatic insufficiency, there was a statistically significant difference in in-hospital mortality [OR = 0.46, 95% CI (0.27 to 0.81), P = 0.007], the occurrence rate of blood transfusions [OR = 0.29, 95% CI (0.22 to 0.38), P < 0.00001] and the occurrence rate of acute kidney injury [OR = 0.55, 95% CI (0.33 to 0.91), P = 0.02]. CONCLUSIONS: TAVI patients with hepatic insufficiency may have negative impact both on short-term (in-hospital or 30-day) and 1-2-years mortality. For patients with hepatic insufficiency, TAVI could be a better option than SAVR.

The Emerging Roles of Extracellular Vesicles in Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest gynecological malignancy. Epithelial ovarian cancer (EOC) is its most common form. OC has both, a poor prognosis and a high mortality rate due to the difficulties of early diagnosis, limitation of current treatment and resistance to chemotherapy. Extracellular vesicles (EVs) is a heterogeneous group of cell-derived submicron vesicles, which can be detected in body fluids, and it can be classified into three main types including exosomes, micro-vesicles, and apoptotic bodies. Cancer cells can produce more EVs than healthy cells. Moreover, the contents of these EVs have been found distinctive from each other. It has been considered that EVs shedding from tumor cells may be implicated in clinical applications, such as a tool for tumor diagnosis, prognosis and potential treatment of certain cancers. In this review, we provide a brief description of EVs. in diagnosis, prognosis, treatment, and drug-resistantance of OC. Cancer-related EVs show powerful influences on tumors by various biological mechanisms. However, the contents mentioned above remain in the laboratory stage and there is a lack of large-scale clinical trials, and the maturity of the purification and detection methods is a constraint. In addition, amplification of oncogenes on ecDNA is remarkably prevalent in cancer. It may be possible that ecDNA can be encapsulated in EVs and thus detected by us. In summary, much more research on EVs needs to be performed to reveal breakthroughs in OC and to accelerate the process of its application in clinic.