Anti-tumor Monoclonal Antibody Research Articles

Linking Effector Function to Antitumor Monoclonal Antibody Efficacy

Abstract This Pillars of Immunology article is a commentary on “Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets”, a pivotal article written by R. A. Clynes, T. L. Towers, L. G. Presta, and J. V. Ravetch, and published in Nature Medicine, in 2000. https://www.nature.com/articles/nm0400_443.

Isolation of anti-tumor monoclonal antibodies targeting on MICA/B α3 domain by single B cell technology for colon cancer therapy

Colon cancer (CC) is one of the most common gastrointestinal malignancies. Effectiveness of the existing therapies is limited. Immunotherapy is a promising complementary treatment approach for CC. Major histocompatibility complex class I-related protein A and B (MICA/B) are ligands for NK cells. Shedding of MICA/B from the surface of tumor cells by cleavage of MICA/B at the membrane proxial region in MICA/B α3 structural domain is one of immune evasion strategies leading to escape of cancer cells from immunosurveillance. In this study, we generated a panel of MICA/B monoclonal antibodies (mAbs) and identified one of mAbs, mAb RDM028, that had high binding affinity to MICA/B and recognized a site on MICA/B α3 structural domain that is critically important for cleavage of MICA/B. Our study has further demonstrated that RDM028 augmented the surface expression of MICA/B on HCT-116 human CC cells by inhibiting the MICA/B shedding resulting in the enhanced cyotoxicity of NK cells against HCT-116 human CC cells and mediated anti-tumor activity in nude mouse model of colon cancer. These results indicate that mAb RDM028 could be explored for developing as an effective immuno therapy against CC by targeting the MICA/B α3 domain to promot immunosurveillance mediated by MICA/B-NKG2D interaction.

#1273 Rapidly progressive glomerulonephritis with anti-neutrophil cytoplasmic antibodies, in a patient on golimumab

Abstract Background 73-year-old Chinese lady presented with fever, gross hematuria, and dysuria of 1-week duration. She has seronegative arthritis and was treated with human anti-tumor necrosis factor alpha monoclonal antibody (TNF-alpha inhibitor), golimumab injection 50 mg monthly, as she had previous adverse reaction with sulfasalazine and methotrexate. She suffered from severe osteoporosis and was treated with oral alendronic acid. At presentation, her blood pressure was 172/76 mmHg and pulse rate 100 beats per minute. The highest recorded temperature was 38.1 degrees Celsius. Clinical examination was unremarkable. She was diagnosed with rapidly progressive glomerulonephritis (RPGN). Creatinine at presentation was 252 µmol/L, estimated glomerular filtration rate (eGFR) 16 mL/min/1.73 m2. Two months ago, her creatinine was 68 µmol/L, eGFR 66 mL/min/1.73 m2. Urinalysis showed dysmorphic red blood cells of more than 2250 per high power field, few white blood cells, and no epithelial cells. Urine protein/creatine ratio (UPCR) was 2.3 g/g and serum albumin level was 30 g/L. ANA was borderline raised at 1:160 titer with homogeneous pattern. Anti-double stranded DNA (anti-dsDNA) was indeterminate at 29.34 IU. Anti-myeloperoxidase (MPO) antibody was positive at 162 RU/mL (Normal < 20 RU/mL). Anti-proteinase-3 (PR3) antibody was negative. Serum complement levels (C3 and C4) were normal. Screening for hepatitis B, hepatitis C, and HIV was negative. Ultrasound imaging of the kidneys showed raised renal echoes and resistive index. Percutaneous kidney biopsy was performed. On light microscopy, 19 glomeruli were seen. Some displayed segmental increase in mesangial cells and expansion of mesangial matrix. 4 glomeruli showed cellular crescents (Fig. 1). Immunofluorescence showed dominant 2+ staining for Immunoglobulin A (IgA) in the mesangium and electron microscopy revealed electron dense deposits in the mesangial and para-mesangial region. An occasional tubuloreticular structure was found. Diagnosis of IgA nephropathy was made and Oxford classification was M0 E1 S0 T0 C1. Results Our patient presented with rapidly progressive glomerulonephritis (RPGN) with positive MPO antibody, as well as ANA and anti-dsDNA at indeterminate levels. TNF-alpha inhibitors may lead to autoantibody formation and kidney biopsy was the key in clinching the diagnosis for our patient. Diagnosis of IgA nephropathy was made on the basis of dominant mesangial IgA on immunofluorescence and ultrastructural electron dense deposits within the mesangial and para-mesangial area. To our best knowledge, there has been only one case of IgA nephropathy reported with golimumab that occurred after 3 years and with mild albuminuria and no decline in renal function. Golimumab was promptly discontinued for our patient and she was inducted with pulsed methylprednisolone and high dose oral prednisolone 1 mg/kg/day. As she had history of severe osteoporosis, oral mycophenolate mofetil at 750 mg twice a day was commenced as steroid sparing agent. Prednisolone dose was then tapered to 0.5 mg/kg/day. She achieved full clinical remission after 3 months of immunosuppressive therapy. MPO antibody level decreased to normal after 5 months. Arthritis activity remained quiescent and she was maintained on low dose prednisolone. Conclusion We report a case of IgA nephropathy with crescents associated with golimumab. Treatment was successful with withdrawal of drug, oral prednisolone and mycophenolate mofetil.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

KIR-генетические факторы и ответ на терапию ингибиторами тирозинкиназ при хроническом миелоидном лейкозе

The development of tyrosine kinase inhibitors (TKIs) and their introduction into clinical practice considerably improved the prognosis for chronic myeloid leukemia (CML) patients. About 50 % of patients with achieved deep molecular response are eligible for safe TKI discontinuation. Despite these advances, no reliable biomarkers are known to predict a response and sustaining treatment-free remission after TKI withdrawal. As TKIs do not destroy leukemic stem cells, which can be responsible for relapse, critical importance in CML is attached to natural killers (NK-cells) having antitumor activity. Functional activity of NK-cells is evaluated by expression level and repertoire of killer cell immunoglobulin-like receptors (KIR). Current studies demonstrate that a patient’s KIR genotype affects the probability of achieving early and deep molecular responses to first- and second-generation TKIs, progression-free and overall survivals, and sustaining treatment-free remission. On that ground, KIR-genetic factors can be regarded as promising predictors of response to TKI therapy in CML. Early clinical studies, which dealt with monoclonal antibodies blocking the inhibitory KIR in order to increase NK-cell activity, revealed an acceptable safety profile and efficacy in some hematological diseases (such as acute myeloid leukemia, multiple myeloma, Т-cell lymphoma) if used in combination with cytostatic drugs or antitumor monoclonal antibodies. KIR genotype determination can contribute to the development of effective therapies of this malignant hematological tumor.

Gastrointestinal Behçet's disease: Manifestations, diagnosis, and management

Behçet's disease (BD) is a rare, inflammatory vascular disorder with recurrent oral and genital aphthous ulcers, along with ocular and cutaneous manifestations. Gastrointestinal (GI) BD may involve any portion of the GI tract. However, it is commonly described in the terminal ileum, followed by the ileocecal region. Diagnosis is challenging given lack of pathognomonic tests; therefore, it is based on clinical criteria. Management of intestinal BD includes different classes of medications including corticosteroids, 5-aminosalicylic acid, immunomodulators, and anti-tumor necrosis factor alpha monoclonal antibody agents. In this review, we aim to focus on intestinal BD and provide details of clinical manifestations, diagnosis and therapeutic options of intestinal BD from gastroenterology viewpoint.

Sustained effect of leukocytapheresis/granulocytapheresis versus anti-human TNF-α monoclonal antibody on ulcerative colitis: A 2-year retrospective study.

Although anti-tumor necrosis factor-α monoclonal antibody biological preparations (BP) agents are widely used as an established treatment tool for refractory ulcerative colitis (UC), whether leukocytapheresis/granulocytapheresis (L/G-CAP) has similar beneficial impact on the disease activity remains undetermined. Furthermore, the costs defrayed for the treatment with these 2 modalities have not been compared. We retrospectively evaluated whether L/G-CAP offered sustained beneficial effects over 2-year period. The patients who had moderately to severely active UC (Rachmilewitz clinical activity index (CAI) ≧ 5) and were treated with a series (10 sessions) of L/G-CAP (n = 19) or BP (n = 7) as an add-on therapy to conventional medications were followed. Furthermore, the cost-effectiveness pertaining to the treatment with L/G-CAP and BP was assessed over 12 months. At baseline, L/G-CAP and BP groups manifested similar disease activity (CAI, L/G-CAP; 7.0 [6.0-10.0], BP; 10.0 [6.0-10.0], P = .207). The L/G-CAP and BP treatment suppressed the activity, with CAI 1 or less attained on day 180. When the L/G-CAP group was dichotomized into L/G-CAP-high and L/G-CAP-low group based on CAI values (≥3 or < 3) on day 365, CAI was gradually elevated in L/G-CAP-high group but remained suppressed in L/G-CAP-low group without additional apheresis for 2 years. Anemia was corrected more rapidly and hemoglobin levels were higher in BP group. The cost of the treatment with L/G-CAP over 12 months was curtailed to 76% of that with BP (1.79 [1.73-1.92] vs 2.35 [2.29-3.19] million yen, P = .028). L/G-CAP is as effective as BP in a substantial number of patients over 2 years. The cost for the treatment of UC favors L/G-CAP although the correction of anemia may prefer BP. Thus, L/G-CAP can effectively manage the disease activity with no additional implementation for 2 years although further therapeutic modalities might be required in a certain population with high CAI observed on day 365.

Anti-tumor necrosis factor-alpha monoclonal antibody suppresses colorectal cancer growth in an orthotopic transplant mouse model.

The risk of malignant tumor progression has been a concern associated with the use of anti-tumor necrosis factor-alpha monoclonal antibody (anti-TNFα mAb). On the contrary, recent observational studies have reported negatively on this risk and instead suggested that anti-TNFα mAb acts as a tumor suppressor in inflammatory carcinogenesis models and subcutaneous transplant models of colorectal cancer. However, no consensus has been established regarding the actual effects of anti-TNFα mAb on malignant tumors. Here, we aimed to evaluate, for the first time, the effect of anti-TNFα mAb on the tumor microenvironment in the absence of intestinal inflammation in a colorectal cancer orthotopic transplant mouse model suitable for tumor microenvironment assessment. The orthotopic transplantation model was developed by transplanting CT26 cells into the cecum of BALB/c mice. Changes in tumor size and weight were recorded 3 weeks after transplantation, and the tumor microenvironment was assessed via RNA sequencing and immunohistological staining. In the orthotopic transplant model, the administration of anti-TNFα mAb led to a reduction in colorectal cancer. The RNA sequencing analysis showed upregulation of immune-related pathways and apoptosis and suppression of stromal- and tumor growth-related pathways. Additionally, Gene Ontology analysis showed inhibition of angiogenesis. Immunohistochemical staining showed inhibition of tumor growth, increase in apoptosis, suppression of stromal response, suppression of angiogenesis, enhancement of tumor immunity, and reduction in the number of tumor-associated macrophages. Anti-TNFα mAb acts as an inhibitor of tumor progression in the tumor microenvironment of a colorectal cancer orthotopic transplant mouse model.

Direct comparison of KATUSHKA far-red fluorescent protein variants with luciferase bioluminescence in xenograft mouse models of epithelial tumor studies

Background. Research in oncology assumes establishment and usage of xenograft animal models, meeting the requirements of humanity and rationality. Although praised as promising field of research, preclinical studies of low-molecular-weight inhibitors, antitumor monoclonal antibodies, vaccines, cellular therapy products, CAR-T cells entail continuous control of tumor growth dynamics. Luciferase detection of bioluminescence requires injection of a reporter substrate. However, injections not only are laborious, time-consuming and expensive, but are also stressful for animals. Thus, a vast variety of new visualization methods is employed, including proteins of the far-red spectrum.Objective. The study aimed to compare detection efficiency of tumor growth dynamics in mice models of cervical cancer, applying a commercially available line of fluorescent red protein derivatives of Katushka clade and Renilla luciferase, that is commonly used in in vivo studies. Design and methods. Xenograft mice models were derived injecting modified HeLa cell line, that expresses fluorescent reporter proteins: Katushka, Katushka2S, TurboRFP, TurboFP650 and Renilla enzyme. Results. Spectral properties and emission wavelength of far-red fluorescent protein Katushka and Katushka2S outlines these markers within RFP derivatives lineage as outstanding instrument for in vivo tumor visualization.Conclusion. Detection of fluorescent far-red reporters Katushka and Katushka2S can be considered as a credible alternative to Renilla luciferase bioluminescence in experimental models in vivo on the part of immunotherapy research.

Seronegative spondyloarthropathy-associated inflammatory bowel disease.

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

IMMUNOLOGICAL CHANGES IN NEWBORN EXPOSED TO ANTI-TNF-A, A PERSPECTIVE.

<h3>Introduction</h3> Anti-TNF drugs have been used extensively for different autoimmune conditions. There is still an existing debate about the use of anti-tumor necrosis factor monoclonal antibodies during pregnancy vis-à-vis their safety and effects on the fetus developing immune system. <h3>Case Description</h3> A 2 month-old boy was born in the setting of a pregnancy during which the mother was being treated with infliximab for Crohn's disease. Weeks after delivery, mom noted a swollen lymph node appeared on the left side of his neck. As well as lymphadenopathy in both groins which subsequently became infected. He underwent incision and drainage of the cervical and groin lymphadenitis. Patient was placed on Keflex. However, during the course of the treatment, he presented recurrent episodes of lymphadenitis requiring a prolonged therapy with Keflex. Upon his evaluation he was alert and afebrile. A large lymph node of about 3 cm over left side of neck and both groins were noted. The left inguinal lymph node was inflamed, infected and oozing pus. An extensive immunological work up was ordered confirming an elevated Infliximab drug level in the patient's serum. Also, the majority of the cytokines evaluated were within normal range even during the course of an active infection. <h3>Discussion</h3> The decision to use anti-TNF-α during pregnancy with the resulting in-utero exposure to the fetus should be discussed with pregnant patients suffering from autoimmunity. Infliximab does interfere with the IL-12/INF-γ making exposed newborns susceptible to repeated infections by causing a temporary condition analogous to a form of primary immunodeficiency.

Tickling APCsThe p84/p110 complex of PI3K regulates NOX2 assembly and cross-presentation of immune complexes

Antibody-mediated cross-presentation is known to elicit strong CD8 + T cell responses, particularly relevant in cancer therapy. Anti-tumor antibodies are known to rapidly kill cancer cells by antibody-dependent cellular cytotoxicity (ADCC), but the long-term immune control of tumors is based on induction of CD8 + T cell response, which relays on anti-tumor antibody-mediated cross-presentation. The molecular mechanisms by which this pathway of cross-presentation allows to poor cross-presenting cells, such as type 2 dendritic cells (DCs) and monocyte-derived DCs (moDCs), to efficiently cross present are not well understood. We demonstrated that enzymatic activity of p84/p110g complex of PI3Kg regulates the assembly of NADPH oxidase NOX2 and ROS production in type 2 DCs from mouse spleen and murine bone marrow derived DCs, enhancing thus the cross-presentation of immune complexes by these cells. Our results suggest that the association between anti-tumor monoclonal antibodies and PI3Kg inhibitors might block the antibody-mediated cross-presentation of tumor antigens and should be avoided in clinical therapy of cancers.

Listeriosis in a Metropolitan Hospital: Is Targeted Therapy a Risk Factor for Infection?

Targeted therapies are widely used for treatment of autoimmune diseases as well as solid organ and hematological malignancies. Various opportunistic infections have been described in patients on targeted therapies. Although case reports or a few case series of listeriosis have been reported to be associated with targeted therapy, most of the cases were related to anti-tumor necrosis factor-α monoclonal antibody. In this study, we describe the epidemiological and clinical profiles of listeriosis in a tertiary hospital in Shenzhen, a Southern Chinese metropolitan city in China. During the 9-year-and-6-month study period, a total of five cases of listeriosis were recorded and all of them had Listeria monocytogenes bacteremia. All five patients had predisposing factors, including corticosteroid (n = 3), targeted therapy (n = 2), pregnancy (n = 2) and anti-interferon gamma autoantibody (n = 1). The two patients who had targeted therapy during their course of cancer treatment received inhibitors of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) pathway. The first one was a 52-year-old woman with metastatic adenocarcinoma of the lung. She was given gefitinib (EGFR tyrosine kinase inhibitor), osimertinib (third-generation EGFR tyrosine kinase inhibitor) and afatinib (tyrosine kinase inhibitor that can bind to EGFR, HER2 and HER4). The second one was a 40-year-old woman with carcinoma of the breast with brain metastasis. She was given trastuzumab (anti-HER2 monoclonal antibody) and lapatinib (dual tyrosine kinase inhibitor of the EGFR/HER2 pathway). These two patients represent the second and third reports of listeria infections associated with EGFR/HER2 pathway inhibitors in the literature. Targeted therapy is an important predisposing factor for listeriosis. Listeria infection is an important differential diagnosis in patients on targeted therapy who present with sepsis and/or central nervous system infection, and the use of antibiotic regimens that cover listeria is crucial for empirical treatment. Avoidance of high-risk food items in these patients is important for the prevention of listeriosis.

The impact of gender and sex in psoriasis: What to be aware of when treating women with psoriasis.

Background:Psoriasis is a common chronic inflammatory skin disease with an exceptionally high burden for women.Objective:Sex-dependent differences in disease manifestation, severity, treatment choices, subjective disease perception, and the impact on quality of life and risk factors are described and comprehensively discussed.Methods:A literature search was conducted using MEDLINE (PubMed) and the Cochrane Library for systematic reviews to investigate the challenges in treating women with psoriasis.Results and conclusions:The incidence, prevalence, and manifestation of psoriasis of the skin are similar between different sexes. Genetic and environmental factors such as obesity and metabolic syndrome are risk factors and are not equally relevant or pronounced in women and men. Overall, women have a lower disease severity measured by the Psoriasis Area Severity Index, which is associated with a higher impairment of their life quality measured by the Dermatology Life Quality Index compared with men. In addition, women with psoriasis are more likely to have depression than men. Hormonal factors affect psoriasis, with a correlation of high estrogen levels and improvement of psoriasis. Data regarding differences in prescribing patterns of systemic treatments and the severity of psoriasis are not entirely consistent. Registry studies show that men tend to have more severe psoriasis and, in some cases, are prescribed systemic therapies more frequently. Women tend to respond better to systemic treatments and to experience more adverse events. Treatment options are the same for both sexes, except during pregnancy and lactation. Various treatment options are contraindicated due to fear of fetal or neonate harm and lack of data. Topical steroids can be prescribed with a high degree of safety during pregnancy. For other topical therapies (calcineurin inhibitors and vitamin D analogs), no studies of adverse effects in pregnancy are available, and safety data mainly stem from studies examining effects after systemic administration. Antitumor necrosis factor monoclonal antibodies (except for certolizumab pegol) have been associated with a possible increased risk of preterm birth, low gestational age, and cesarean deliveries. Prospective data on the safety of biologics other than antitumor necrosis factor-alpha antibodies to accurately assess whether novel biologics (eg, anti-interleukin 17, 12/23, 23) can be used for systemic therapy in pregnancy are lacking or currently being conducted.

Biologic therapy for Crohn's disease over the last 3 decades.

BACKGROUNDDespite the overload of publications on Crohn’s disease (CD), no comprehensive analysis of biologic therapy for CD has been reported.AIMTo determine knowledge gaps and identify areas of interest of biologic therapy for CD.METHODSThe top 100 highest-cited original articles were identified from January 1991 to December 2020 in the Clarivate Analytics Web of Science Core Collection database. We conducted a bibliometric analysis of biologic therapy for CD based on total citations, summarized the bibliographic information of the articles related to CD biologic therapy, and explored the research hotspots.RESULTSThe top 100 highest-cited original articles were identified with total citations ranging from 307 to 2978. The 2000s (Period II, n = 66) yielded the most influential original articles and saw the most dramatic growth. Among the top 10 countries, including 8 European countries and 2 North American countries, the United States (n = 37) and Belgium (n = 20) contributed the most publications. Among the top 10 institutions, the University Hospital Gasthuisberg in Belgium (n = 23), the University of Chicago in the United States (n = 20), and the Mayo Clinic in the United States (n = 17) published the most papers. Regarding authors, Rutgeerts P in Belgium (n = 32), Sandborn WJ in the United States (n = 23), and Feagan BG in Canada (n = 18) published the highest number of studies. The cooperation relationships between the United States and Europe were most frequent. Gastroenterology (impact factor = 22.682) published the most articles on biologic therapy for CD (n = 32) with 17654 total citations. Anti-tumor necrosis factor biologics and monoclonal antibodies were the most studied topics.CONCLUSIONThe bibliometric analysis emphasized the key contributions to the development of the specialized field. These data would provide useful research insights into biologic therapy for CD for clinicians and researchers.

Minimal change nephrotic syndrome due to certolizumab pegol, an anti-tumor necrosis factor-alpha monoclonal antibody for treatment of rheumatoid arthritis.

Minimal change nephrotic syndrome due to certolizumab pegol, an anti-tumor necrosis factor-alpha monoclonal antibody for treatment of rheumatoid arthritis.

Blood glucose related adverse drug reaction of antitumor monoclonal antibodies: a retrospective analysis using Vigibase

On the increasing prevalence of using mAbs (monoclonal antibodies) in cancer therapy and the severe risk of hyperglycemia, we aimed to analyze the main clinical ADRs of mAbs, with a focus on adverse hyperglycemic events associated with currently clinically used mAbs. mAbs as well as target information were selected from Martinadale book and published articles. Drug approving information was collected from each government website, and ADR statistic data were collected from VigibaseR, comparing with Adverse Event Reporting System of US FDA. Top 10 mAbs were classified within listing in total ADR records, ADRs per year, hyperglycemic ADR records. Vigibase data were updated onto 15 Feb 2019. 20 mAbs were analyzed with 263217 ADR reports, wherein 16751 records on Metabolism and nutrition disorders and 1444 records on Glucose metabolism disorders. The geographic, age, gender distributions and annual ADR report numbers were listed respectively. Of the top 10, Rituximab, Bevacizumab and Nivolumab were on the top 3 in total ADR record and hyperglycemic record. Top 3 record results were similar in Vigibase and FDA database. It is of increasing importance for clinicians to be aware of early detection, patient management, or drug selection strategies when using mAbs, particularly within the high glycemic risk-reported mAbs, to improve the efficacy and tolerability of mAbs regiment and optimize patient outcomes.

A Pilot Phase I Trial of IL-21 Expanded Ideal-Donor Natural Killer (NK) Cells in Combination with Mogamulizumab in Patients with Cutaneous T-Cell Lymphomas (CTCL) or Adult T-Cell Leukemia/Lymphomas (ATLL)

A Pilot Phase I Trial of IL-21 Expanded Ideal-Donor Natural Killer (NK) Cells in Combination with Mogamulizumab in Patients with Cutaneous T-Cell Lymphomas (CTCL) or Adult T-Cell Leukemia/Lymphomas (ATLL)

Enhancement of anti-TNFα monoclonal antibody production in CHO cells through the use of UCOE and DHFR elements in vector construction and the optimization of cell culture media

Recently, there has been a high demand for anti-tumor necrosis factor-α monoclonal antibodies (mAbTNFα) in the treatment of rheumatoid arthritis and other autoimmune diseases. Thus, efficient strategies and stable high-producing cell lines need to be established to increase antibody production. In this study, we describe an efficient approach to establish a mAbTNFα high-producing clone through the optimization of expression vectors and cell culture media. The ubiquitous chromatin opening element (UCOE) and dihydrofolate reductase (DHFR)-based vectors encoding mAbTNFα were introduced into the CHO-DG44 cells using lipofection. Clones were obtained by selecting transfected cells with G418, amplifying them by treatment with methotrexate, and isolating them by limiting dilution. Different media formulated with commercial feeds and media were also screened to develop an improved medium. The antibody produced by the selected clone was purified, characterized, and compared to standard adalimumab. Using our established protocol, a cell clone obtained from stable mAbTNFα-expressing cell pools showed a 3.8-fold higher antibody titer compared to stable cell pools. Furthermore, the highest antibody yield of selected clones cultured in fed-batch mode using improved medium was 2450 ± 30 µg/mL, which was 13.2-fold higher than that of stable cell pool cultivated in batch mode using a basal medium. The purified antibody had primary chemical and biological characteristics similar to those of adalimumab. Therefore, the use of UCOE and DHFR vectors in combination with the optimization of cell culture media may help in establishing stable and high-producing CHO cell lines for therapeutic antibody production.

Juvenile Idiopathic Arthritis-Associated Chronic Uveitis: Recent Therapeutic Approaches.

Pediatric patients with early onset (before the age of 6 years), antinuclear antibody positive, oligoarticular or polyarticular juvenile idiopathic arthritis (JIA), and some children with no arthritis may develop chronic, anterior uveitis. Recent recommendations insist on the need to perform slit lamp examination every 3 months for at least 5 years in early onset JIA patients in order to diagnose uveitis before complications develop. Local steroid therapy is usually the first-line treatment. However, in patients requiring steroid eye drops for several months, systemic immunomodulatory therapy is indicated. Methotrexate (MTX) is then prescribed in most cases; however, some patients also need anti-tumor necrosis factor alpha monoclonal antibody therapy and, in some cases, other biologics to control uveitis and avoid long-term ocular damage. Expert ophthalmologists and pediatricians must be involved in taking care of such patients. Immunomodulatory treatment must not be too easily interrupted and may even be intensified in some cases, particularly if there is a need for optimal disease control before ophthalmologic surgery. In good responders to MTX and/or biologics, treatment must be maintained at least 1 year, possibly even 2 years after achieving remission before tapering treatment intensity.