Recombinant Human Interleukin-11 Research Articles

Real-World Evidence of Hetrombopag for Cancer Therapy-Induced Thrombocytopenia Among Patients with Gynecologic Malignancies

Background: Despite the widespread use of platinum-based combination chemotherapy, particularly when complemented with taxanes, for the treatment of gynecologic malignancies, its administration often results in myelosuppression. This effect can be potentiated across cumulative chemotherapy cycles, thereby inducing a more persistent condition known as cancer therapy-induced thrombocytopenia (CTIT). Traditionally, preferred treatments for CTIT entail platelet transfusion or the use of recombinant human thrombopoietin (rhTPO), or recombinant human interleukin-11 (rhIL-11). However, the efficacy of platelet transfusion tends to decrease with repetitive administration, and it carries inherent risks of infectious diseases. Additionally, rhIL-11 may induce severe hypersensitivity reactions, necessitating permanent discontinuation of the drug. Emerging as an appealing alternative, thrombopoietin-receptor agonists (TPO-RAs) present a promising approach for CTIT treatment. Among these, hetrombopag, an orally administered small-molecule TPO-RA, has demonstrated notable platelet-boosting effects and a favorable safety profile not only in patients with immune thrombocytopenia and severe aplastic anemia but also in those suffering from persistent CTIT. This study aims to appraise the real-world effectiveness and safety of hetrombopag, administered either alone or in conjunction with other platelet-boosting agents, for the management of CTIT in patients diagnosed with gynecologic malignancies. Methods: In this retrospective study conducted from January 2022 to June 2023, we examined the role of hetrombopag in treating CTIT among patients with gynecologic malignancies. The patients, aged 18 years and above, had experienced thrombocytopenia (platelet counts<100×10 9/L) following platinum-based chemotherapy or other antitumor treatments and subsequently received hetrombopag either as monotherapy or in combination with other platelet-boosting agents, such as rhTPO or rhIL-11. The primary outcome was platelet response within 14 days, denoted by a recovery in platelet counts to ≥100×10 9/L or an increase of ≥50×10 9/L or at least double from the baseline. Results: This study comprised 38 patients, with 55.3% diagnosed with ovarian cancer, 36.8% with cervical cancer, 5.3% with endometrial cancer, and 2.6% with other types. The median age was 58 years, with the majority (73.7%) at clinical stages III/IV. As for the antitumor regimens, 89.5% incorporated platinum, 68.4% included taxanes, 26.3% used antiangiogenic agents, and 15.8% employed PD-1 inhibitors. Among the patients, 15.8% received hetrombopag 2.5 mg/day monotherapy, while the remainder received hetrombopag in combination with rhTPO or rhIL-11. Baseline platelet counts prior to hetrombopag therapy averaged 46.5±24.9×10 9/L. Encouragingly, the 14-day platelet response rate was 71.1%, with a median time to response of 10 days (95% confidence interval, 5-14). Following treatment with hetrombopag, patients exhibited a gradual increase in platelet levels, recording mean platelet counts of 48.7, 67.1, 95.5, 108.5, 146.5, and 131.9×10 9/L on days 3, 5, 7, 9, 11, and 14 respectively. Importantly, hetrombopag was well-tolerated, with no treatment-related adverse events observed during the treatment course. Conclusion: In conclusion, our findings suggest hetrombopag, either alone or in combination with other therapies, displays preliminary effectiveness and safety in treating CTIT. Given its convenient oral administration and promising platelet-boosting effects observed in this study, prospective investigations of hetrombopag monotherapy for CTIT in gynecologic malignancies are warranted.

298 Interleukin-6 Family Members Improve Pre-Implantation Bovine Blastocyst Composition

Abstract Inner cell mass (ICM) size is a predictor of bovine blastocyst quality and post-transfer pregnancy success. In vitro produced (IVP) embryos have reduced ICM cell numbers compared with in vivo produced embryos, and we propose this is one reason pregnancy success is compromised in IVP embryos. Our recent work found that human recombinant interleukin-6 (IL6) supplementation during in vitro embryo culture increased ICM cell numbers. We hypothesized that other human recombinant members of the IL6 cytokine family, specifically interleukin-11 (IL11) and leukemia inhibitory factor (LIF), will have a similar response. In vitro maturation, fertilization and culture procedures were used to produce embryos that were treated with 100 ng/mL recombinant human recombinant IL6, IL11, LIF, or carrier [control; 1% (wt/vol) SOF-BSA] beginning at day 6 post-fertilization (25 embryos/50 mL drop; 3 drops/treatment; 5 replicates). A subset of day 8 blastocysts (n = 28 to 29) was fixed and processed for cell counting. Analyses were performed by least-squares ANOVA using the general linear model. No treatment differences in overall blastocyst rates, trophectoderm (TE) cell numbers, and total cell numbers were observed at day 8. Treatment with IL6 (P = 0.09) and LIF (P = 0.06) tended to increase ICM cell numbers when compared with the control, whereas IL11 was not different from the control. Treatment with IL6 increased the ICM:TE ratio (P < 0.05) but the other cytokines did not influence this ratio. Several treatment by stage interactions were observed. In regular day 8 blastocysts (n = 10 to 14), none of the treatments affected ICM numbers or the ICM:TE ratio, but LIF increased TE number (P < 0.05) and IL6 increased total cell number (P < 0.05). When grouping expanded and hatched blastocysts together (n = 14 to 18), each treatment increased ICM cell numbers and IL6 increased the ICM:TE ratio (P < 0.05). Furthermore, both IL11 (P = 0.08) and LIF (P = 0.08) tended to increase the ICM:TE ratio. Only LIF increased total cell numbers (P < 0.05). None of the other treatments affected total cell numbers. These observations suggest that IL6, IL11, and LIF are capable of influencing ICM cell numbers in IVP bovine embryos, but they may possess different abilities in affecting TE and overall cell numbers. These findings differ from previous findings from our lab. We suspect that transitioning from bovine recombinant preparations with undefined purity and bioactivity to using purified human recombinant proteins with high bioactivity allowed us to detect these responses for each cytokine. Collectively, this work implicates several members of the IL6 cytokine family as embryokines that may be used to improve bovine IVP embryo quality. Funding for this work was provided by USDA-NIFA (2017-67015-2646 and 2021-67015-34485) and by NIH (R21-OD026516-01).

Efficacy and Safety of Avatrombopag on Thrombocytopenia after Chemotherapy in Acute Leukaemia

Background: Thrombocytopenia following chemotherapy is a common and serious complication that leads to an increased risk of bleeding and poor prognosis for patients with acute leukaemia. Current therapeutic strategies consist of platelet transfusion, recombinant human interleukin-11(rhIL-11) and recombinant human thrombopoietin (rhTPO) injection, but these strategies are not satisfactory for some patients and the treatment remains challenging. Avatrombopag is a novel thrombopoietin receptor agonist, which had been approved for thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a surgery in the USA, Europe, and China, and in patients with chronic immune thrombocytopenia who were unresponsive to previous treatments in the USA and Europe. This study aims to determine the efficacy and safety of avatrombopag on thrombocytopenia after chemotherapy of acute leukaemia, and to increase the evidence for clinical use of avatrombopag. Methods: The clinical data of 24 acute leukaemia patients with grade 3/4 chemotherapy-induced thrombocytopenia (CIT) for 3-28 days were collected from February 2022 to February 2023. All patients received avatrombopag orally at a dose of 40 mg / day. Platelet (PLT) transfusion was allowed when the platelet level was less than 20×10 9/L or with bleeding events. If platelet count increased to 100 ×10 9/L or 50 ×10 9/L more than baseline, which was defined as complete response (CR), treatment of avatrombopag was stopped. Results: The median age of 24 patients with CIT was 38 (range 17‒69) years, with 14 patients diagnosed with acute myeloid leukemia (AML), 9 patients diagnosed with acute lymphoblastic leukemia (ALL), and 1 patient diagnosed with mixed phenotype acute leukemia (MPAL). Chemotherapy regiments for patients with AML included decitabine combined with venetoclax (n=5), decitabine combined with arabinoside (n=3), arsenic trioxide combined with retinoic acid (n=3), azacytidine combined with venetoclax (n=2), azacytidine combined with medium-dose arabinoside (n=1). Chemotherapy regiments for patients with ALL included CD19 specific CAR-T cells (n=3), decitabine (n=2), blinatumomab (n=2), IVP (idarubicin, vindesine, and prednisone) (n=1), azacytidine combined with venetoclax and chidamide (n=1). Chemotherapy regiment for the patient with MPAL was decitabine combined with venetoclax (n=1). At baseline, 10 patients experienced grade 3 thrombocytopenia after chemotherapy, while 14 patients experienced grade 4 thrombocytopenia after chemotherapy. The median lowest platelet count was 19×10 9/L (range 1-47×10 9/L). During the treatment period, 14 patients received platelet transfusion. The median time to reach the CR standard was 6 (range 3-26) days, and no patients stopped treatment due to side effect or drug intolerance. Compared with using avatrombopag before, the levels of platelet count were significantly increased ( P=0.000 1). The optimal platelet count of 22 patients reached the standard of CR after 7 days of drug withdrawal. Conclusion: Avatrombopag is effective on increasing platelet counts in patients with acute leukaemia after chemotherapy, with a good safety profile. It is a suitable therapeutic option for thrombocytopenia after chemotherapy.

Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction.

Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor β (TGFβ) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFβ stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

Efficacy of recombinant human interleukin-11 in preventing and treating oral mucositis after chemotherapy for patients with acute leukemia

ObjectiveThis study aimed to investigate the clinical effects of recombinant human interleukin-11 (rhIL-11) gargle on preventing and treating oral mucositis (OM) after chemotherapy for acute leukemia.MethodsThis single-site, prospective, observer-blinded, nonrandomized controlled trial was conducted on 74 patients with acute leukemia, who were divided into the experimental and control groups. The patients in the experimental group were treated with IL-11 gargle, and those in the control group were treated with sodium bicarbonate gargle. We examined the time and severity of oral mucositis, severity and duration of associated pain, healing time of mucositis, effects of OM on eating, and levels of T-cell subset indicators before and after treatment to evaluate the effects of IL-11 treatment.ResultsThe proportion of patients with severe OM was significantly lower in the experimental group than in the control group. Mucositis occurred later in the experimental group compared with the control group. The degree and duration of pain, ulcer healing time, and effects on eating were lower in the experimental group compared with the control group. Following treatment, the levels of all T-cell subset indicators improved in each of the two groups. However, the rate of improvement was significantly higher in the experimental group than in the control group. These differences were statistically significant (P < 0.05).ConclusionsIL-11 gargle reduced the severity of OM after chemotherapy for acute leukemia. Treatment with IL-11 relieved pain, promoted healing, and improved the curative effect of the condition, making it worthy of clinical promotion.

Anti-apoptosis effect of recombinant human interleukin-11 in neonatal hypoxic-ischemic rats through activating the IL-11Rα/STAT3 signaling pathway

Hypoxia-ischemia (HI) is one of the most common causes of death and disability in neonates. Apoptosis contributes to HI development. Interleukin-11(IL-11) has been shown to protect mice from cerebral ischemia/reperfusion injury. However, whether IL-11 exerts the anti-apoptotic effect on HI injury is unclear. In this study, we demonstrated that recombinant human IL-11 (rhIL-11) prevented apoptosis of rat neonates with HI through activating IL-11Rα/STAT3 signaling. Sprague-Dawley rat pups on the 7th day after birth were used to establish an HI injury model. The expression levels of IL-11Rα and GP130 were increased first and then decreased after HI. In contrast, IL-11 expression was first decreased and then increased. Immunofluorescence staining showed that IL-11Rα was localized in neurons and oligodendrocytes. RhIL-11 treatment alleviated hippocampal and cortical damages, significantly reduced cerebral infarction volumes, cerebral edema, and loss of the Nissl body and nerve cells, and also ameliorated the outcomes of HI injury and long-term neurological deficits. In addition, rhIL-11 treatment upregulated the expressions levels of Bcl-2 and p-STAT3/STAT3, and downregulated the protein concentrations of the lytic protease, and cleaved-caspase-3. Furthermore, GP130 inhibitor and JAK1 inhibitor reversed the protective effects of rhIL-11. Overall, rhIL-11 showed an anti-apoptosis effect on the brain after HI injury. Our results indicated that rhIL-11 reduced neuronal apoptosis by activating the brain IL-11Rα/STAT3 pathway.

Cost-effectiveness analysis of rhTPO and rhIL-11 in the treatment of chemotherapy-induced thrombocytopenia in hematological tumors based on real-world data

Chemotherapy-induced thrombocytopenia (CIT) is a common adverse reaction to chemotherapy that can lead to treatment delay, platelet transfusion, thereby increasing treatment costs, reducing chemotherapy effectiveness and affecting prognosis. Based on real-world data, this study analyzed the safety, efficacy, and economic of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of CIT in hematological tumors from the perspective of the health care system.We retrospectively collected the data of hematological tumor patients treated with rhTPO and rhIL-11 due to thrombocytopenia caused by chemotherapy. The propensity score matching (PSM) method was used to balance the baseline information of the two groups and they were further stratified according to the degree of thrombocytopenia (grade I-II and grade III-IV). The platelet compliance rate at 2 weeks of treatment was used as the efficacy evaluation index, and the cost-effectiveness method was used to evaluate the economic value of the two drugs in the treatment of thrombocytopenia based on drug effectiveness. Univariate and probabilistic sensitivity analyses were performed.A total of 1,571 patients met the inclusion and exclusion criteria, and 476 patients were included after 1:1 PSM. For patients with grade I-II thrombocytopenia, no significant difference in the platelet compliance rate was found between the two groups after 1 and 2 weeks of treatment. The platelet compliance rate in the rhTPO group was higher than that in the rhIL-11 group for patients with grade III-IV thrombocytopenia. Cost-effectiveness analysis (CEA) showed that the incremental cost-effectiveness ratio (ICER) for the rhTPO and rhIL-11 groups was 226,615.8. The ICER value was sensitive to the platelet compliance rate of the two groups, the cost of rhTPO, the cost of platelet transfusion in the rhTPO group. Probabilistic sensitivity analysis showed that when willingness to pay was less than approximately 220,000 yuan, rhIL-11 economy presented 100% better than that of rhTPO.In CIT treatment for hematological tumors, rhTPO yielded a higher platelet compliance rate than rhIL-11 treatment, especially for patients with grade III-IV thrombocytopenia. However, whether rhTPO has economic advantages still requires further exploration.

A prospective interventional study of recombinant human interleukin-11 mouthwash in chemotherapy-induced oral mucositis

BackgroundThis prospective interventional study aimed to evaluate and analyse the efficacy of rhIL-11 mouthwash compared to Kangfuxin fluid in treatment and blank control in prevention of oral mucositis (OM) in patients receiving chemotherapy.Materials and MethodsIn total, 50 patients in the treatment group and 62 patients in the prevention group were included. Subsequently, each group was divided into an experimental group and a control group. In the treatment group, the experimental patients received recombinant human interleukin-11 (rhIL-11) mouthwash, whereas the control group received Kangfuxin fluid. In the prevention group, experimental patients still received rhIL-11 mouthwash based on routine oral care, whereas the control group only received routine oral care. Meanwhile, we observed and recorded the efficacy in the treatment group, and the occurrence and grades of OM in the prevention group.ResultsThrough statistical analysis, the results showed that on the seventh day of treatment, the experimental group showed more improvement compared to the control group, and it was statistically significant (p = 0.032). The average healing time in the experimental group (3.59 ± 1.927 days) was shorter than that in the control group (4.96 ± 2.421 days; p = 0.031). In the prevention group, we observed the incidence of oral mucositis. No significant differences were found in the occurrence and grades of OM in the experimental and control groups (p = 0.175).ConclusionOur preliminary results indicate that rhIL-11 mouthwash may be a superior option to treat OM, especially in severe cases, compared to Kangfuxin fluid. However, there is no advantage in prevention.

Effect of rhTPO and rhIL-11 on Thrombocytopenia after Chemotherapy in Leukemia

To analyze and compare the efficacy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin-11 (rhIL-11) in the treatment of thrombocytopenia after chemotherapy in acute leukemia patients. 180 patients with acute leukemia complicated with thrombocytopenia after chemotherapy in the First Affiliated Hospital of Anhui Medical University were analyzed retrospectively. Among them, 50 patients who treated with rhTPO and did not receive platelet transfusion were set as group A, 50 patients treated with rhTPO and receive platelet transfusion were set as group B, Forty patients treated with rhIL-11 without platelet transfusion were set as group C, Forty patients who treated with rhIL-11 and received platelet transfusion were set as group D. The duration of PLT below 20×109/L, the days it takes for PLT to recover to more than 100×109/L, and the incidence of different bleeding degrees were compared among several groups. The duration of PLT<20×109/L in group A(3.72±1.14 d) was significantly shorter than that in group C(4.93±1.33 d) (P<0.001), and there was no significant difference from group B (P>0.05). The duration of PLT<20×109/L in group B(3.06±0.91 d) was significantly shorter than that in group D(4.65±0.98 d) (P<0.001), while the difference in duration of days between group C and D was not statistically significant (P>0.05). The times for PLT to recover to 100×109/L in group A(13.46±1.67 d) were significantly shorter than that in group C(16.85±2.13 d) (P<0.05), but there was no significant difference from group B (P>0.05). The time required for PLT to recover to 100×109/L in group B(13.36±1.49 d) were significantly shorter than that in group D(16.18±1.78 d) (P<0.05), while the difference in the days required for group C and group D was not statistically significant (P>0.05). The incidence of high bleeding risk in group B was significantly lower than that in group A (22% vs 44%, P<0.05), the incidence of high bleeding risk in group D was significantly lower than that in group C (32% vs 65%, P<0.05), and the incidence of high bleeding risk in group A was significantly lower than that in group C (44% vs 65%, P<0.05). The incidence of high bleeding risk in group B(22%) was lower than that in group D(32.5%), and the difference was not statistically significant (P>0.05). In the treatment of acute leukemia patients with thrombocytopenia after chemotherapy, compared with rhIL-11, rhTPO can significantly shorten the duration for patients in a status with extremely low levels of PLT and the recovery time of PLT to normal range. In addition, PLT transfusion cannot speed up the time for patients to raise platelets to a safe range, nor can it shorten the duration of low PLT levels, but it can reduce the incidence of high bleeding risk events.

Analysis of Agranulocytosis Time and Its Influencing Factors in Patients with Hematological Malignancies Treated with rhIL-11 combined rhG-CSF

To explore the intervention effect of recombinant human interleukin-11 (rhIL-11) and recombinant human granulocyte-colony stimulating factor (rhG-CSF) on the duration and severity of agranulocytosis in patients with hematological malignancies after chemotherapy, and to analyze the influencing factors. The data of hematological malignancy patients treated with rhIL-11 and rhG-CSF after chemotherapy in the hematology department of The First Hospital of Lanzhou University from July 2017 to July 2020 were collected retrospectively. The duration and differences of agranulocytosis in differeent groups were compared by univariate analysis, and the influencing factors of agranulocytosis duration were further analyzed by multiple regression analysis. The duration of agranulocytosis in 97 patients was 6.47±2.93 days. The results of univariate analysis showed that there were no statistical differences in the duration of agranulocytosis among patients with different sex, age, height, weight, body surface area, body mass index (BMI), dose of rhG-CSF, dose of rhIL-11, spontaneous bleeding after administration of rhG-CSF and rhIL-11, and the duration of agranulocytosis in patients with different red blood cell count (RBC), hemoglobin(HGB) level, platelet count (PLT) and absolute neutrophil count (ANC), before administration of rhG-CSF and rhIL-11. There were significant differences in agranulocytosis time among patients with different disease types, chemotherapy cycle, fever after rhG-CSF and rhIL-11 administration, and different white blood cell count (WBC) baseline level before rhG-CSF and rhIL-11 administration (P＜0.05). Compared with patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), patients with acute myeloid leukemia (AML) had the longest duration of agranulocytosis, which was 7.07±3.05 d. Compared with patients with chemotherapy cycles of 4－6 and ≥7, patients with total chemotherapy cycle of 1－3 had the shortest duration of agranulocytosis, which was 5.25±2.48 d. Compared with patients without fever, patients with fever within 1 day after administration of cytokines and patients with fever within 2-5 days after administration of cytokines, the duration of agranulocytosis was the longest in patients with fever 6 days after administration of cytokines, which was 8.85±2.85 d. Compared with patients with WBC baseline <1.0×109/L, (1.0－1.9)×109/L and (2.0－3.9)×109/L, patients with WBC baseline ≥4.0×109/L had the shortest duration of agranulocytosis, which was 4.50±2.56 d. Multiple linear regression analysis showed that chemotherapy cycle, different fever after administration of rhG-CSF and rhIL-11, diagnosis of ALL and NHL, and WBC baseline level before administration of rhG-CSF and rhIL-11 were the influencing factors of the duration of agranulocytosis (P＜0.001). The risk of prolonged agranulocytosis is higher in patients diagnosed with AML, with more chemotherapy cycles, lower WBC baseline before cytokines administration and fever later after cytokines administration, which should be paid more attention to.

Facile production of tag-free recombinant human interleukin-11 by transforming into soluble expression in Escherichia coli

Human interleukin-11 (IL-11) is considered as a difficult-to-express protein in prokaryotic expression systems because of its low expression level and high tendency to form inclusion bodies. The current source of recombinant human IL-11 (rhIL-11) for therapeutic use is mainly obtained from a fusion protein synthesized by Escherichia coli, which requires an additional operation to cleave the fusion tag. Herein, we reported a strategy for the direct expression of tag-free rhIL-11 in E. coli. To explore the soluble expression of rhIL-11 without fusion tags in E. coli, we inserted the rhIL-11 gene into a pBV220 plasmid which is characterized by employing a temperature-sensitive pR/pL promoter to manipulate the transcription and translation of the gene of interest. As a result, the tag free rhIL-11 was efficiently expressed in the soluble form in E. coli. A two-step chromatography method, Capto Butyl-S combined with Capto Q, was developed to efficiently purify the tag-free rhIL-11 from the supernatant of the cell lysate. The resultant rhIL-11 showed a compact and highly ordered structure, as validated by circular dichroism and intrinsic fluorescence emission spectra. Additionally, the biological activity of the purified rhIL-11 was evaluated by TF-1 cell proliferation experiments and the results demonstrated that the E. coli expressed rhIL-11 is biologically active.

A Randomized Placebo-Controlled Trial of Recombinant Human Interleukin-11 in Cancer Patients With Severe Thrombocytopenia Due To Chemotherapy

Thrombocytopenia is a complication of cancer treatment that can limit dose intensity. Interleukin-11 (IL-11) is a growth factor that increases platelet production. We conducted a multicenter, randomized, placebo-controlled trial of recombinant human IL-11 (rhIL-11) in 93 patients with cancer who had already been transfused platelets for severe thrombocytopenia resulting from chemotherapy. The patients had received platelet transfusions for nadir platelet counts of < or = 20,000/microL during the chemotherapy cycle immediately preceding study entry. Chemotherapy was continued during the study without dose reduction. Patients were randomized to receive placebo or rhIL-11 at 50 or 25 micrograms/kg subcutaneously once daily for 14 to 21 days beginning 1 day after chemotherapy. Eight of 27 (30%) evaluable patients treated with rhIL-11 at a dose of 50 micrograms/kg did not require platelet transfusions versus 1 of 27 (4%) patients who received placebo (P < .05). Five of 23 (18%) patients treated with rhIL-11 at 25 micrograms/kg avoided platelet transfusions (P = .23). Side effects were fatigue and cardiovascular symptoms, including a low incidence of atrial arrhythmias and syncope. There were no differences among treatment groups in the incidence of neutropenic fever, days of hospitalization, or number of red blood cell transfusions. This study shows that rhIL-11 treatment of a dose of 50 micrograms/kg significantly increases the likelihood that patients who have already been transfused platelets for severe chemotherapy-induced thrombocytopenia will not require platelet transfusions during a subsequent chemotherapy cycle.

Recombinant Human IL-11 Promotes Lung Adenocarcinoma A549 Cell Growth and EMT through Activating STAT3/HIF-1α/EMT Signaling Pathway.

Interleukin-11 (IL-11) could promote invasion and metastasis of cancer cells, however, its mechanism is unclear. This study aimed to investigate the effects of recombinant human IL-11 (rhIL-11) on lung cancer cell metastasis and growth. Human lung cancer cell, A549, was cultured and subcutaneously injected into mice to establish Xenograft tumor models. Tumor models were divided into control, rhIL-11 transplantation (250 μg/kg/day), and rhIL-11 transplantation (500 μg/kg/day) group. Tumor volumes were recorded and measured 6 times. Hypoxia- Inducible Factor 1α (HIF1α), snail, slug, Signal Transducers/Activators of Transcription-3 (STAT3), E-cadherin, twist, and vimentin levels were evaluated using western blot and Real-Time PCR (RT-PCR). Sizes of subcutaneous tumors increased following measurement time. rhIL-11 treatment significantly enhanced HIF1α and STAT3 expression in rhIL-11 treatment groups compared to the control group (p<0.05). However, no remarkable differences were discovered between rhIL-11 (250 μg/kg/day) and rhIL-11 (500 μg/kg/day) group (p>0.05). rhIL-11 treatments significantly increased twist, and slug expressions compared to control group (p<0.05), especially for rhIL-11 (500 μg/kg/day) treatment, which triggered significantly higher effects on twist and slug expressions compared to those in the control group (p<0.05). Vimentin and snail mRNA levels were significantly up-regulated and E-cadherin level was significantly down-regulated in rhIL-11 treatment groups compared to the control group (p<0.05). Meanwhile, rhIL-11 at a dosage of 500 μg/kg/day triggered remarkably higher effects on vimentin, snail, and E-cadherin expressions compared to those in rhIL-11 (250 μg/kg/day) group (p<0.05). rhIL-11 transplantation promoted growth and Epithelial-Mesenchymal Transition (EMT) of A549 cells, which might be associated with STAT3/HIF-1α/EMT signaling pathway activation.

A case of acute cardiac insufficiency induced by recombinant human interleukin-11

A case of acute cardiac insufficiency induced by recombinant human interleukin-11

Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys

AimProtein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys. Main methodsEnzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys. Key findingsThe results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1–0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure. SignificanceThese methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.

MiR-495 and miR-5688 are down-regulated in non-small cell lung cancer under hypoxia to maintain interleukin-11 expression.

BackgroundHypoxia is a hallmark of cancer and is associated with poor prognosis. However, the molecular mechanism by which hypoxia promotes tumor progression remains unclear. MicroRNAs dysregulation has been shown to play a critical role in the tumor and tumor microenvironment. Here, we investigated the roles of miR‐495 and miR‐5688 in human non‐small cell lung cancer (NSCLC) and their underlying mechanism.MethodsThe expression levels of miR‐495 and miR‐5688 in human NSCLC tissue specimens were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR). Deferoxamine (DFO) was used to determine whether the regulation of miR‐495 and miR‐5688 under hypoxia was dependent on hypoxia‐inducible factor 1‐alpha (HIF‐1α). Furthermore, the functions of miR‐495 and miR‐5688 in tumor progression were evaluated using colony formation, 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium (MTS), wound healing, transwell assays, and xenograft model. Two algorithms, PicTAR and Targetscan, were used to predict the target gene of these two miRNAs, and dual‐luciferase reporter assay was conducted to confirm the target. The unpaired two‐tailed t test, Pearson correlation analysis, and Fisher's exact probability test were performed for statistical analyses.ResultsTwo miRNAs, miR‐495 and miR‐5688, were found to participate in NSCLC progression under hypoxia. They were down‐regulated in NSCLC tissues compared with normal tissues. We determined that hypoxia led to the down‐regulation of miR‐495 and miR‐5688 in NSCLC cells, which was independent of HIF‐1α and cellular metabolic energy. In addition, miR‐495 and miR‐5688 suppressed cell proliferation, migration, and invasion in vitro. The NSCLC xenograft model showed that miR‐495 and miR‐5688 inhibited tumor formation in vivo. Interestingly, we found that miR‐495 and miR‐5688 had the same target, interleukin‐11 (IL‐11). Recombinant human IL‐11 counteracted the effects of miR‐495 and miR‐5688 on NSCLC cells, suggesting that miR‐495 and miR‐5688 executed their tumor suppressive role by repressing IL‐11 expression.ConclusionWe found that hypoxia down‐regulated the expression levels of miR‐495 and miR‐5688 in NSCLC to enhance IL‐11 expression and tumor progression, indicating that the miR‐495/miR‐5688/IL‐11 axis may serve as a therapeutic target and potential biomarker for NSCLC.

Effect of Recombinant Human Interleukin-11 on Oral Mucositis Associated with Allogeneic Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation gives new life to malignant hematologic patient. However, oral mucositis caused by graft-versus-host disease affects the quality of life of patients. Objective: To observe the efficacy of recombinant human interleuko-11 in the treatment of allogeneic hematopoietic stem cell transplantation associated with oral mucositis. Methods: 54 patients requires an allogeneic hematopoietic stem cell transplantation in patients with hematological clinical observation research, the control group was 0.05% acetic acid chloride solution is folinic acid joint and diluent containing wash, the experimental group on the basis of the join recombinant human interleukin - 11 atomization and contain gargle, comparing curative effect, the ulcer healing time and pain, anxiety and depression scores, as well as oral infections. Results: the efficacy of recombinant human interleukin-11 treatment group was better than that of control group (X2=4.43; P = 0.035); Nebulized inhalation and gargle containing recombinant human interleuk-11 significantly reduced the mean healing days of oral ulcers (Experimenta group A vs. control group C, P=0.05, P=0.004, P=0.000). Experimental group B vs. control group C, P=0.045, P=0.005, P=0.000) and can reduce the occurrence of pain and bad mood. Conclusion: recombinant human interleukin-11 is effective in the treatment of oral mucositis associated with allogeneic hematopoietic stem cell transplantation. It can effectively shorten the course of disease and reduce the incidence of oral infection, anxiety and depression while reducing the pain of patients.

Efficacy and safety of recombinant human interleukin-11 in the treatment of acute leukaemia patients with chemotherapy-induced thrombocytopenia: A systematic review and meta-analysis.

Current meta-analysis was conducted aiming to assess the efficacy and safety of recombinant human interleukin-11 (rhIL-11) in the treatment of acute leukaemia (AL) patients with chemotherapy-induced thrombocytopenia (CIT). We searched PubMed, Embase, Chinese National Knowledge Infrastructure database (CNKI), Cochrane Library, and Wan Fang Database on 4 July 2018. Ten randomized controlled trials (RCTs) and two observational studies were included, which involved 754 AL patients with CIT. Pooled analysis demonstrated that rhIL-11 was beneficial on CIT: recovery time of platelet count to 50×109 /L [weight mean difference (WMD)=-4.19 days; 95% CI: -5.01, -3.37], recovery time of platelet count to 100×109 /L (WMD=-4.45days; 95% CI: -4.85, -4.06), platelet transfusion volume (WMD=-6.14U; 95% CI: -9.20, -3.09), and the rate of haemorrhage (RR=0.46; 95% CI: 0.36 to 0.61). Most adverse events associated with rhIL-11 were mild to moderate. Our findings suggest that rhIL-11 is effective and safe in the treatment of CIT in patients with AL.

Platelet and peripheral white blood cell counts at diagnosis predict the response of adult immune thrombocytopenia to recombinant human interleukin-11: A retrospective, single-center, case-control study.

This study evaluated the effectiveness of recombinant human interleukin-11 (rhIL-11) in the treatment of immune thrombocytopenia (ITP) and determined whether clinical and laboratory findings predicted the treatment response.This retrospective, single-center, case–control study included 103 adult patients with ITP treated between July 2010 and April 2014 at Jiangxi Province People's Hospital. About 49 patients in the pred+IL group received prednisone (conventional dose) combined with an rhIL-11 regimen, and 54 patients in the pred alone group received prednisone (conventional dose) alone. Demographic data, initial and follow-up platelet counts, proportions of patients achieving platelet counts ≥30 × 109/L (response) and ≥100 × 109/L (complete response) at different time points, and adverse reactions were compared between groups.Complete response rates were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Proportions of patients achieving response or complete response at different time points were similar between groups overall but higher in the pred+IL group than in the pred alone group for newly diagnosed patients and those with severe ITP (P < .05). Posttreatment platelet count correlated negatively with platelet count at diagnosis and white blood cell (WBC) count at diagnosis in patients with newly diagnosed ITP (r = −0.337, P = .073 and r = −0.367, P = .050, respectively) or ITP with bleeding-related episodes (r = −0.357, P = .020 and r = −0.434, P = .004, respectively). No immediate or postinfusion severe adverse reactions were observed.rhIL-11 increased CR and improved hemostasis in patients with newly diagnosed or severe ITP. Platelet and WBC counts at diagnosis can predict the response to rhIL-11.

Elevated BNP caused by recombinant human interleukin-11 treatment in patients with chemotherapy-induced thrombocytopenia

Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes and often induced by chemotherapy. Recombinant human interleukin-11 (rhIL-11) is a cytokine that can stimulate thrombopoiesis and is commonly used to treat thrombocytopenia. We observed the side effects of rhIL-11 in 24 leukemia patients with chemotherapy-induced thrombocytopenia. To determine the cardiovascular effects of rhIL-11, we detected changes in the patients’ serum brain natriuretic peptide (BNP), blood pressure fluctuations, weight change, and whether edema or heart failure occurred in leukemia patients after chemotherapy. The results showed that BNP was significantly elevated after using rhIL-11 (P < 0. 05) but regressed after 2–4 days. Furthermore, nine patients had edema and experienced weight gain, and four experienced acute left heart failure. In addition, the average blood pressure was 119/75 mmHg (range 139/86 mmHg to 99/64 mmHg) before rhIL-11 administration and 127/79 mmHg (range 146/89 mmHg to 108/69 mmHg) after rhIL-11 use. In conclusion, although rhIL-11 is useful for treating chemotherapy-induced thrombocytopenia, it is important to monitor the patients’ clinical status and re-examine BNP levels frequently during the use of rhIL-11. Furthermore, senile patients should be given special attention. However, the appropriate timing to begin and discontinue rhIL-11 treatment needs further investigation.