Fully human monoclonal antibodies (mAbs) are a promising and rapidly growing category of targeted therapeutic agents. The first such agents were developed during the 1980s, but none achieved clinical ...or commercial success. Advances in technology to generate the molecules for study - in particular, transgenic mice and yeast or phage display - renewed interest in the development of human mAbs during the 1990s. In 2002, adalimumab became the first human mAb to be approved by the US Food and Drug Administration (FDA). Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab. In addition, 3 candidates (raxibacumab, belimumab and ipilimumab) are currently under review by the FDA, 7 are in Phase III studies and 81 are in either Phase I or II studies. Here, we analyse data on 147 human mAbs that have entered clinical study to highlight trends in their development and approval, which may help inform future studies of this class of therapeutic agents.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Middle East respiratory syndrome (MERS) coronavirus causes a highly fatal lower-respiratory tract infection. There are as yet no licensed MERS vaccines or therapeutics. This study (WRAIR-2274) ...assessed the safety, tolerability, and immunogenicity of the GLS-5300 MERS coronavirus DNA vaccine in healthy adults.
This study was a phase 1, open-label, single-arm, dose-escalation study of GLS-5300 done at the Walter Reed Army Institute for Research Clinical Trials Center (Silver Spring, MD, USA). We enrolled healthy adults aged 18–50 years; exclusion criteria included previous infection or treatment of MERS. Eligible participants were enrolled sequentially using a dose-escalation protocol to receive 0·67 mg, 2 mg, or 6 mg GLS-5300 administered by trained clinical site staff via a single intramuscular 1 mL injection at each vaccination at baseline, week 4, and week 12 followed immediately by co-localised intramuscular electroporation. Enrolment into the higher dose groups occurred after a safety monitoring committee reviewed the data following vaccination of the first five participants at the previous lower dose in each group. The primary outcome of the study was safety, assessed in all participants who received at least one study treatment and for whom post-dose study data were available, during the vaccination period with follow-up through to 48 weeks after dose 3. Safety was measured by the incidence of adverse events; administration site reactions and pain; and changes in safety laboratory parameters. The secondary outcome was immunogenicity. This trial is registered at ClinicalTrials.gov (number NCT02670187) and is completed.
Between Feb 17 and July 22, 2016, we enrolled 75 individuals and allocated 25 each to 0·67 mg, 2 mg, or 6 mg GLS-5300. No vaccine-associated serious adverse events were reported. The most common adverse events were injection-site reactions, reported in 70 participants (93%) of 75. Overall, 73 participants (97%) of 75 reported at least one solicited adverse event; the most common systemic symptoms were headache (five 20% with 0·67 mg, 11 44% with 2 mg, and seven 28% with 6 mg), and malaise or fatigue (five 20% with 0·67 mg, seven 28% with 2 mg, and two 8% with 6 mg). The most common local solicited symptoms were administration site pain (23 92% with all three doses) and tenderness (21 84% with all three doses). Most solicited symptoms were reported as mild (19 76% with 0·67 mg, 20 80% with 2 mg, and 17 68% with 6 mg) and were self-limiting. Unsolicited symptoms were reported for 56 participants (75%) of 75 and were deemed treatment-related for 26 (35%). The most common unsolicited adverse events were infections, occurring in 27 participants (36%); six (8%) were deemed possibly related to study treatment. There were no laboratory abnormalities of grade 3 or higher that were related to study treatment; laboratory abnormalities were uncommon, except for 15 increases in creatine phosphokinase in 14 participants (three participants in the 0·67 mg group, three in the 2 mg group, and seven in the 6 mg group). Of these 15 increases, five (33%) were deemed possibly related to study treatment (one in the 2 mg group and four in the 6 mg group). Seroconversion measured by S1-ELISA occurred in 59 (86%) of 69 participants and 61 (94%) of 65 participants after two and three vaccinations, respectively. Neutralising antibodies were detected in 34 (50%) of 68 participants. T-cell responses were detected in 47 (71%) of 66 participants after two vaccinations and in 44 (76%) of 58 participants after three vaccinations. There were no differences in immune responses between dose groups after 6 weeks. At week 60, vaccine-induced humoral and cellular responses were detected in 51 (77%) of 66 participants and 42 (64%) of 66, respectively.
The GLS-5300 MERS coronavirus vaccine was well tolerated with no vaccine-associated serious adverse events. Immune responses were dose-independent, detected in more than 85% of participants after two vaccinations, and durable through 1 year of follow-up. The data support further development of the GLS-5300 vaccine, including additional studies to test the efficacy of GLS-5300 in a region endemic for MERS coronavirus.
US Department of the Army and GeneOne Life Science.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background With increasing prevalence of injected drug use in the United States, a growing number of intravenous drug users (IVDUs) are at risk for infective endocarditis (IE) that may ...require surgical intervention; however, few data exist about clinical outcomes of these individuals. Methods We evaluated consecutive adult patients undergoing surgery for active IE between 2002 and 2014 pooled from 2 prospective institutional databases. Death and valve-related events, including reinfection or heart valve reoperation, thromboembolism, and anticoagulation-related hemorrhage were evaluated. Results Of the 436 patients identified, 78 (17.9%) were current IVDUs. The proportion of IVDUs increased from 14.8% in 2002 to 2004 to 26.1% in 2012 to 2014. IVDUs were younger (aged 35.9 ± 9.9 years vs 59.3 ± 14.1 years) and had fewer cardiovascular risk factors than non-IVDUs. During follow-up (median, 29.4 months; quartile 1-3, 4.7-72.6 months), adverse events among all patients included death in 92, reinfection in 42, valve-reoperation in 35, thromboembolism in 17, and hemorrhage in 16. Operative mortality was lower among IVDUs (odds ratio, 0.25; 95% confidence interval CI, 0.06-0.71), but overall mortality was not significantly different (hazard ratio HR, 0.78; 95% CI, 0.44-1.37). When baseline profiles were adjusted by propensity score, IVDUs had higher risk of valve-related complications (HR, 3.82; 95% CI, 1.95-7.49; P < .001) principally attributable to higher rates of reinfection (HR, 6.20; 95% CI, 2.56-15.00; P < .001). Conclusions The proportion of IVDUs among surgically treated IE patients is increasing. Although IVDUs have lower operative risk, long-term outcomes are compromised by reinfection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Monoclonal antibodies (mAbs) are an increasingly important class of therapeutic agents. Although fewer antibody fragments have entered the clinic than full-length monoclonal antibodies, ...proof-of-concept studies for these therapeutics remain the main hurdle.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The birth iron endowment provides iron for growth in the first months of life. We describe the iron endowment under conditions of low dietary iron supply. Subjects were infants participating in a ...trial of Vitamin D supplementation from 1 to 9 months. Infants were exclusively breastfed at enrollment but could receive complementary foods from 4 months but not formula. Plasma ferritin (PF) and transferrin receptor (TfR) were determined at 1, 2, 4, 5.5, 7.5, 9 and 12 months. At 1 month PF ranged from 38 to 752 µg/L and was only weakly related to maternal PF. PF declined subsequently and flattened out at 5.5 months. PF of females was significantly higher than PF of males except at 12 months. TfR increased with age and was inversely correlated with PF. PF and TfR tracked strongly until 9 months. Iron deficiency (PF < 10 µg/L) began to appear at 4 months and increased in frequency until 9 months. Infants with ID were born with low iron endowment. We concluded that the birth iron endowment is highly variable in size and a small endowment places infants at risk of iron deficiency before 6 months. Boys have smaller iron endowments and are at greater risk of iron deficiency than girls.
XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations ...instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging.
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•The DNA repair nuclease XPG has a non-catalytic role in HRR and genome stability•XPG depletion causes DSBs, chromatid breaks, and camptothecin and PARPi sensitivity•XPG partners with key HRR proteins BRCA1, BRCA2, PALB2, and RAD51 to effect HRR•XPG loss reduces homologous recombination and increases stalled replication forks
It is unclear how the loss of XPG protein causes the neurodevelopmental disorder Cockayne syndrome with death in early childhood. Trego et al. show that XPG partners with BRCA1 and BRCA2 to maintain genomic stability through homologous recombination, and its loss causes DNA breaks, chromosome aberrations, and replication fork stalling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:Thrombelastography (TEG) fibrinolysis shutdown after trauma is associated with increased mortality due to hypercoagulability-associated organ failure. However, a lack of mechanistic data ...has precluded the development of novel interventions to treat shutdown.
OBJECTIVES:To define the pathophysiology of TEG shutdown in severely injured, bleeding patients through secondary analysis of the PROPPR trial.
METHODS:Fibrinolysis was characterized in PROPPR subjects using admission TEG lysis at 30 min (LY30) or plasmin-antiplasmin (PAP) levels. LY30 categories were low (<0.9%), moderate (0.9–2.9%), or high (≥ 3%). PAP was classified as low (<1,500 μg/L), moderate (1,500–20,000 μg/L), or high (>20,000 μg/L). Demographics, outcomes, admission TEG values, platelet count and function, standard coagulation tests, and coagulation proteins were compared.
RESULTS:Five hundred forty-seven patients had TEG data and 549 patients had PAP data available. Low LY30 was associated with reduced platelet count and aggregation, poorer TEG clot formation, prolonged clotting times, and reduced fibrinogen and alpha2 antiplasmin. Compared to moderate PAP, low PAP subjects had similar platelet parameters, TEG values, fibrinogen, and alpha2 antiplasmin, but reduced tPA, and elevated PAI-1. D-Dimer values increased as PAP increased, however patients with low LY30 had elevated D-Dimer compared with moderate LY30 patients. Most low LY30 deaths were due to TBI (45%) and hemorrhage (42%) versus one of each cause (TBI, hemorrhage, MOF) in low PAP patients.
CONCLUSIONS:Low TEG LY30 does not reflect shutdown of enzymatic fibrinolysis with hypercoagulability, but rather a coagulopathic state of moderate fibrinolysis with fibrinogen consumption and platelet dysfunction that is associated with poor outcomes.
Breastfed infants require supplementation with vitamin D (vD), but little is known about the necessary dose. This double blind trial evaluated four different doses of vD.
Exclusively breastfed ...infants (N = 213) were randomized at 1 mo to one of four doses, which they received through 9 mo while receiving no formula. The supplements provided daily 200 IU, 400 IU, 600 IU, or 800 IU of vD. The primary endpoint was plasma 25(OH)D level, and secondary outcomes were plasma parathyroid hormone and calcium, and illness incidence. The study was conducted during winter at 41° N.
Most infants had low (<50 nmol/l) 25(OH)D levels at 1 mo, but with supplementation levels rose. Overall, levels of 25(OH)D differed significantly in proportion to vD dose. There were no effects of vD on illness incidence or growth. Low levels were common, with 7.8% of levels being <50 nmol/l and 15 infants having 2 to 4 low levels.
The four doses of vD produced different plasma levels of 25(OH)D. The higher doses were somewhat more efficacious in maintaining vD sufficiency in breastfed infants. The findings support the recommended dose of 400 IU/d, and stress the need to start supplementation at birth.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive ...packed RBC transfusion.
We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Subjects in the parent trial included critically injured adult patients admitted to 1 of 12 North American Level I trauma centers who received at least 1 unit of packed RBCs and were predicted to require massive blood transfusion. The primary exposure was volume of packed RBC units transfused during the first 24 hours of hospitalization, stratified by packed RBC age category: 0 to 7 days, 8 to 14 days, 15 to 21 days, and greater than or equal to 22 days. The primary outcome was 24-hour mortality. We evaluated the association between transfused volume of each packed RBC age category and 24-hour survival, using random-effects logistic regression, adjusting for total packed RBC volume, patient age, sex, race, mechanism of injury, Injury Severity Score, Revised Trauma Score, clinical site, and trial treatment group.
The 678 patients included in the analysis received a total of 8,830 packed RBC units. One hundred patients (14.8%) died within the first 24 hours. On multivariable analysis, the number of packed RBCs greater than or equal to 22 days old was independently associated with increased 24-hour mortality (adjusted odds ratio OR 1.05 per packed RBC unit; 95% confidence interval CI 1.01 to 1.08): OR 0.97 for 0 to 7 days old (95% CI 0.88 to 1.08), OR 1.04 for 8 to 14 days old (95% CI 0.99 to 1.09), and OR 1.02 for 15 to 21 days old (95% CI 0.98 to 1.06). Results of sensitivity analyses were similar only among patients who received greater than or equal to 10 packed RBC units.
Increasing quantities of older packed RBCs are associated with increased likelihood of 24-hour mortality in trauma patients receiving massive packed RBC transfusion (≥10 units), but not in those who receive fewer than 10 units.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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