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121.
122.
Xiufeng Wu Arlene J Sereno Flora Huang Steven M Lewis Ricky L Lieu Caroline Weldon Carina Torres Cody Fine Micheal A Batt Jonathan R Fitchett Andrew L Glasebrook Brian Kuhlman Stephen J Demarest 《MABS-AUSTIN》2015,7(3):470-482
A myriad of innovative bispecific antibody (BsAb) platforms have been reported. Most require significant protein engineering to be viable from a development and manufacturing perspective. Single-chain variable fragments (scFvs) and diabodies that consist only of antibody variable domains have been used as building blocks for making BsAbs for decades. The drawback with Fv-only moieties is that they lack the native-like interactions with CH1/CL domains that make antibody Fab regions stable and soluble. Here, we utilize a redesigned Fab interface to explore 2 novel Fab-based BsAbs platforms. The redesigned Fab interface designs limit heavy and light chain mixing when 2 Fabs are co-expressed simultaneously, thus allowing the use of 2 different Fabs within a BsAb construct without the requirement of one or more scFvs. We describe the stability and activity of a HER2×HER2 IgG-Fab BsAb, and compare its biophysical and activity properties with those of an IgG-scFv that utilizes the variable domains of the same parental antibodies. We also generated an EGFR × CD3 tandem Fab protein with a similar format to a tandem scFv (otherwise known as a bispecific T cell engager or BiTE). We show that the Fab-based BsAbs have superior biophysical properties compared to the scFv-based BsAbs. Additionally, the Fab-based BsAbs do not simply recapitulate the activity of their scFv counterparts, but are shown to possess unique biological activity. 相似文献
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124.
John K. Thuita Kristina K. Wolf Grace A. Murilla Arlene S. Bridges David W. Boykin James N. Mutuku Qiang Liu Susan K. Jones Charles O. Gem Shelley Ching Richard R. Tidwell Michael Z. Wang Mary F. Paine Reto Brun 《PLoS neglected tropical diseases》2015,9(2)
Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. 相似文献
125.
Background
Cytochrome P450 2D6 (CYP2D6) gene duplication and multiplication can result in ultrarapid drug metabolism and therapeutic failure or excessive response in patients. Long range polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing are usually used for genotyping CYP2D6 duplication/multiplications and identification, but are labor intensive, time consuming, and costly.Methods
We developed a simple allele quantification-based Pyrosequencing genotyping method that facilitates CYP2D6 copy number variation (CNV) genotyping while also identifying allele-specific CYP2D6 CNV in heterozygous samples. Most routine assays do not identify the allele containing a CNV. A total of 237 clinical and Coriell DNA samples with different known CYP2D6 gene copy numbers were genotyped for CYP2D6 *2, *3, *4, *6, *10, *17, *41 polymorphisms and CNV determination.Results
The CYP2D6 gene allele quantification/identification were determined simultaneously with CYP2D6*2, *3, *4, *6, *10, *17, *41 genotyping. We determined the exact CYP2D6 gene copy number, identified which allele had the duplication or multiplication, and assigned the correct phenotype and activity score for all samples.Conclusions
Our method can efficiently identify the duplicated CYP2D6 allele in heterozygous samples, determine its copy number in a fraction of time compared to conventional methods and prevent incorrect ultrarapid phenotype calls. It also greatly reduces the cost, effort and time associated with CYP2D6 CNV genotyping. 相似文献126.
127.
Meeting the projected 50% increase in global grain demand by 2030 without further environmental degradation poses a major challenge for agricultural production. Because surface ozone (O3) has a significant negative impact on crop yields, one way to increase future production is to reduce O3‐induced agricultural losses. We present two strategies whereby O3 damage to crops may be reduced. We first examine the potential benefits of an O3 mitigation strategy motivated by climate change goals: gradual emission reductions of methane (CH4), an important greenhouse gas and tropospheric O3 precursor that has not yet been targeted for O3 pollution abatement. Our second strategy focuses on adapting crops to O3 exposure by selecting cultivars with demonstrated O3 resistance. We find that the CH4 reductions considered would increase global production of soybean, maize, and wheat by 23–102 Mt in 2030 – the equivalent of a ~2–8% increase in year 2000 production worth $3.5–15 billion worldwide (USD2000), increasing the cost effectiveness of this CH4 mitigation policy. Choosing crop varieties with O3 resistance (relative to median‐sensitivity cultivars) could improve global agricultural production in 2030 by over 140 Mt, the equivalent of a 12% increase in 2000 production worth ~$22 billion. Benefits are dominated by improvements for wheat in South Asia, where O3‐induced crop losses would otherwise be severe. Combining the two strategies generates benefits that are less than fully additive, given the nature of O3 effects on crops. Our results demonstrate the significant potential to sustainably improve global agricultural production by decreasing O3‐induced reductions in crop yields. 相似文献
128.
Gillingwater K Gutierrez C Bridges A Wu H Deborggraeve S Ekangu RA Kumar A Ismail M Boykin D Brun R 《PloS one》2011,6(6):e20836
Three diamidines (DB 75, DB 867 and DB 1192) were selected and their ability to cure T. evansi experimentally infected goats was investigated. A toxicity assessment and pharmacokinetic analysis of these compounds were additionally carried out. Goats demonstrated no signs of acute toxicity, when treated with four doses of 1 mg/kg/day (total dose 4 mg/kg). Complete curative efficacy of experimentally infected goats was seen in the positive control group treated with diminazene at 5 mg/kg and in the DB 75 and DB 867 groups treated at 2.5 mg/kg. Drug treatment was administered once every second day for a total of seven days. Complete cure was also seen in the group of goats treated with DB 75 at 1.25 mg/kg. DB 1192 was incapable of curing goats at either four-times 2.5 mg/kg or 1.25 mg/kg. Pharmacokinetic analysis clearly demonstrated that the treatment failures of DB 1192 were due to sub-therapeutic compound levels in goat plasma, whilst compound levels for DB 75 and DB 867 remained well within the therapeutic window. In conclusion, two diamidine compounds (DB 75 and DB 867) presented comparable efficacy at lower doses than the standard drug diminazene and could be considered as potential clinical candidates against T. evansi infection. 相似文献
129.
Joseph Keawe‘aimoku Kaholokula Claire K.M. Townsend Arlene Ige Ka‘imi A. Sinclair Marjorie K. Mau Anne Leake Donna‐Marie Palakiko Sheryl R. Yoshimura Puni Kekauoha Claire Hughes 《Obesity (Silver Spring, Md.)》2013,21(3):E196-E203
Objective:
Native Hawaiians and other Pacific Islanders (NHs/PIs) have a high obesity prevalence compared to other ethnic groups. We examined socio‐demographic, behavioral, and biological factors related to ≥3% weight loss in 100 overweight/obese NHs/PIs who completed a lifestyle intervention.Design and Methods:
Data were from 56 Native Hawaiians, 22 Chuukese, and 22 Other Pacific Islanders who participated in a randomized controlled trial of the Partnership for Improving Lifestyle Intervention (PILI) 'Ohana Project. All completed a 3‐month weight loss program (WLP) to initiate weight loss and were then randomized into either a 6‐month family/community focused WLP called the PILI Lifestyle Program (PLP; n = 49) or a standard behavior WLP (SBP; n = 51). We collected baseline, 3‐ and 9‐month follow‐up data on socio‐demographics, weight (kg), a 6‐min. walk test, dietary fat, exercise frequency, and blood pressure.Results and Conclusion:
Based on ANCOVA or logistic fit, ethnicity, sex, initial weight loss, fat in diet at baseline, change in systolic blood pressure, and intervention type were significantly associated (P ≤ .05) with ≥3% weight loss at 9‐month follow‐up. A logistic regression model indicated that Chuukese (OR = 6.04; CI = 1.14–32.17) and participants who had more weight loss in the first 3‐months (OR = 1.47; CI = 1.22–1.86) and who were in the PLP (OR = 4.50; CI = 1.50–15.14) were more likely to achieve ≥3% weight loss [model; χ2 (7, N = 100) = 45.50, P < .0001]. The same lifestyle intervention does not benefit all NHs/PIs equally, possibly due to differences in acculturation status and social support. The findings also point to the importance of initial weight loss to sustain motivation toward long‐term weight loss maintenance. 相似文献130.
Hadi Maazi Abinav K. Singh Anneliese O. Speak Vincent Lombardi Jonathan Lam Bryant Khoo Kyung Soo Inn Arlene H. Sharpe Jae U. Jung Omid Akbari 《PloS one》2013,8(3)
There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1−/−-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2−/−-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza. 相似文献