Fc effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) are crucial to the efficacy of many antibody therapeutics. In addition to IgG, antibodies of the IgA isotype can also promote cell killing through engagement of myeloid lineage cells via interactions between the IgA-Fc and FcαRI (CD89). Herein, we describe a unique, tandem IgG1/IgA2 antibody format in the context of a trastuzumab variable domain that exhibits enhanced ADCC and ADCP capabilities. The IgG1/IgA2 tandem Fc format retains IgG1 FcγR binding as well as FcRn-mediated serum persistence, yet is augmented with myeloid cell-mediated effector functions via FcαRI/IgA Fc interactions. In this work, we demonstrate anti-human epidermal growth factor receptor-2 antibodies with the unique tandem IgG1/IgA2 Fc can better recruit and engage cytotoxic polymorphonuclear (PMN) cells than either the parental IgG1 or IgA2. Pharmacokinetics of IgG1/IgA2 in BALB/c mice are similar to the parental IgG, and far surpass the poor serum persistence of IgA2. The IgG1/IgA2 format is expressed at similar levels and with similar thermal stability to IgG1, and can be purified via standard protein A chromatography. The tandem IgG1/IgA2 format could potentially augment IgG-based immunotherapeutics with enhanced PMN-mediated cytotoxicity while avoiding many of the problems associated with developing IgAs.

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To compare health care resource utilization and treatment patterns between patients with actinic keratosis (AK) treated with ingenol mebutate gel (IngMeb) and those treated with other field-directed AK therapies.
A retrospective, propensity-score-matched, cohort study compared refill/repeat and adding-on/switching patterns and outpatient visits and prescriptions (health care resource utilization) over 6 months in patients receiving IngMeb versus those receiving imiquimod, 5-fluorouracil, diclofenac sodium, and methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT).
The final sample analyzed included four matched treatment cohort pairs (IngMeb and comparator; n = 790-971 per treatment arm). Refill rates were similar except for imiquimod (15% vs. 9% for imiquimod and IngMeb, respectively; P < 0.05). MAL/ALA-PDT treatment repetition rates were higher than IngMeb refill rates (20% vs. 10%; P < 0.05). Topical agent add-on/switch rates were comparable. PDT had higher switch rates than did IngMeb (5% vs. 2%; P < 0.05). The IngMeb cohort had a significantly lower proportion of patients with at least one AK-related outpatient visit during the 6-month follow-up than did any other cohort: versus imiquimod (50% vs. 66%; P < 0.0001), versus 5-fluorouracil (50% vs. 69%; P < 0.0001), versus diclofenac sodium (51% vs. 56%; P = 0.034), and versus MAL/ALA-PDT (50% vs. 100%; P < 0.0001). There were significantly fewer AK-related prescriptions among patients receiving IngMeb than among patients in other cohorts.
Results based on the first 6 months after treatment initiation suggested that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with higher refill rates, and PDT, which was associated with significantly more frequent treatment sessions and higher switching rates. IngMeb was also associated with significantly fewer outpatient visits than were other field-directed therapies.
Copyright © 2016. Published by Elsevier Inc.

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Health care decisions are complex and involve confronting trade-offs between multiple, often conflicting objectives. Using structured, explicit approaches to decisions involving multiple criteria can improve the quality of decision making. A set of techniques, known under the collective heading, multiple criteria decision analysis (MCDA), are useful for this purpose. In 2014, ISPOR established an Emerging Good Practices Task Force. The task force’s first report defined MCDA, provided examples of its use in health care, described the key steps, and provided an overview of the principal methods of MCDA. This second task force report provides emerging good-practice guidance on the implementation of MCDA to support health care decisions. The report includes: a checklist to support the design, implementation and review of an MCDA; guidance to support the implementation of the checklist; the order in which the steps should be implemented; illustrates how to incorporate budget constraints into an MCDA; provides an overview of the skills and resources, including available software, required to implement MCDA; and future research directions.
Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

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To investigate the relationship between effective fentanyl sublingual spray (FSS) doses for breakthrough cancer pain (BTCP) and around-the-clock (ATC) transdermal fentanyl patch (TFP).
Adults tolerating ATC opioids received open-label FSS for 26 days, followed by a 26-day double-blind phase for patients achieving an effective dose (100-1600 µg).
Out of 50 patients on ATC TFP at baseline, 32 (64%) achieved an effective dose. FSS effective dose moderately correlated with mean TFP dose (r = 0.4; p = 0.03). Patient satisfaction increased during the study. Common adverse event included nausea (9%) and peripheral edema (9%).
FSS can be safely titrated to an effective dose for BTCP in patients receiving ATC TFP as chronic cancer pain medication. ClinicalTrials.gov identifier: NCT00538850.

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Inhibition of the V600E mutated BRAF kinase gene (BRAF(V600E) ) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF(V600E) , PLX3603, showed potent melanoma growth-inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of (18) F-FDG and (18) F-FLT-PET to monitor the early effects of the BRAF(V600E) inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF(V600E) , received the BRAF(V600E) inhibitor twice daily orally (0, 25, 50 and 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of (18) F-FDG and (18) F-FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial (18) F-FDG and (18) F-FLT-PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF(V600E) inhibitor. A dose-dependent decrease in (18) F-FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased (18) F-FDG uptake in A375 tumors (41, 35 and 51%, respectively). (18) F-FLT uptake in the A375 tumors was low at baseline and no significant changes in (18) F-FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo (18) F-FDG and (18) F-FLT-PET imaging. These data demonstrate that (18) F-FDG-PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603.
Copyright © 2014 John Wiley & Sons, Ltd.

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