Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) I, the slow delayed rectifier current; 2) I, the rapid delayed rectifier current; and 3) I, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

KCNQ1 (Kv7.1) is a unique member of the superfamily of voltagegated K + channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different β subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of β subunits using voltage-clamp fluorometry (VCF). In our previous study, we found the kinetics and voltage dependence of voltage-sensor movements are very similar to those of the channel gate, as if multiple voltage-sensor movements are not required to precede gate opening. Here, we have tested two different hypotheses to explain KCNQ1 gating: (i) KCNQ1 voltage sensors undergo a single concerted movement that leads to channel opening, or (ii) individual voltage-sensor movements lead to channel opening before all voltage sensors have moved. Here, we find that KCNQ1 voltage sensors move relatively independently, but that the channel can conduct before all voltage sensors have activated. We explore a KCNQ1 point mutation that causes some channels to transition to the open state even in the absence of voltage-sensor movement. To interpret these results, we adopt an allosteric gating scheme wherein KCNQ1 is able to transition to the open state after zero to four voltage-sensor movements. This model allows for widely varying gating behavior, depending on the relative strength of the opening transition, and suggests how KCNQ1 could be controlled by coassembly with different KCNE family members.) is a member of the superfamily of voltagegated potassium channels (K V ), which contain six transmembrane helices and form functional tetramers with four peripheral voltage-sensing domains surrounding a single potassiumselective pore domain (1). Much study spanning recent decades has focused on the detailed gating mechanisms of these molecular machines, establishing general principles of K V channel gating, as well as unique structural and functional properties that underlie the diverse physiological functions of different family members (2). Within the K V family, KCNQ1 displays a unique flexibility in its gating properties, depending on the tissue where it is expressed and the corresponding β subunit with which it coassembles: in the intestine KCNQ1/KCNE3 channels display voltage-independent current that supports chloride secretion (3), whereas in the heart, KCNQ1/KCNE1 channels display slowly activating voltage-dependent current that is critical to cardiac action potential repolarization (4-6). Remarkably, neither of these physiologically essential phenotypes resembles that of the KCNQ1 channel expressed alone, which activates rapidly over a hyperpolarized range of voltages (4, 5). Still other KCNE proteins coassemble with KCNQ1 to form heteromeric channels with distinct biophysical characteristics (7,8). This diverse array of gating schema allows this protein to play unique important roles in a vast number of systems in the body, including the heart, brain, inner ear, ...

Background Pembrolizumab is a potent, humanized, monoclonal anti–programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. Patients and methods Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non–small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. Results Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA–positive; none had neutralizing antibodies. Conclusions The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. Trial registration ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015). ...

Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review. The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 μg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 μg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC. Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. .