TPS765 Background: PT886 is a novel bispecific antibody that targets Claudin 18.2 (CLDN18.2) and CD47. CLDN18.2 is overexpressed in a significant proportion of gastric and pancreatic adenocarcinomas and its restricted expression makes it a promising therapeutic target for the treatment of these carcinomas. Moreover, studies have found that immunoglobulin superfamily CD47 is overexpressed widely across tumor types, and CD47 plays an important role in suppressing phagocytes activity through binding to the transmembrane protein SIRPα in phagocytic cells. Hence, by targeting both pathways, one can direct macrophage-mediated phagocytotic activity to tumor cells by blocking the “don’t eat me” signal mediated by CD47/ SIRPα interaction, potentially offering a better safety profile than anti-CD47 monoclonal antibodies. Additionally, PT886 utilizes IgG1 to enhance antibody-dependent cellular cytotoxicity (ADCC) by NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages and thus increases the antitumor activity. The combined cancer killing effects by the above mechanisms therefore represent a novel approach in treating CLDN18.2-positive malignancies. Methods: This is an open label, Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PT886 in subjects with unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC) for which there is no available standard therapy. Approximately 34-58 patients will be enrolled. The study consists of 2 parts: Dose Escalation, and Dose Expansion. The dose escalation study of PT886 will be guided by a standard 3+3 dose escalation study design to determine the maximum tolerated dose (MTD) and/or the optimal biological doses for expansion. The MTD or the optimal biological dose and a lower dose level will be further evaluated in a dose expansion cohort to determine a recommended phase II dose (RP2D). Each enrolled patient will receive PT886 as a monotherapy (0.1, 0.3, 1, 3 or 6 mg/kg QW) as an intravenous infusion continuously (over 60 minutes) in 28-day cycles. The primary endpoints are Dose Limiting Toxicity (DLT) and MTD, if reached, and RP2D of PT886 as a single agent. PD markers of PT886 biological activity will be measured, including T-cell receptor sequencing on circulating T cells, T-cell activation studies, serum cytokines and assessing CLDN18.2 expression in tumor tissues. PT886, which was recently granted orphan drug designation by the FDA for the treatment of pancreatic cancer, has the potential to be a new treatment option for pancreatic and gastric cancer patients whose current standard of care is limited. Preliminary safety and efficacy data are anticipated in the second quarter of 2023. Clinical trial information: NCT02178241 .

Background PT199 is an anti-CD73 monoclonal antibody (mAb) with a differentiated mechanism of action. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering antitumor immune cells more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors. PT199 fully inhibits both soluble and membrane-bound CD73, unlike some other CD73 inhibitors which may inhibit only one form of enzyme or exhibit incomplete inhibition. Moreover, at higher concentrations no loss of inhibition or "hook effect" is observed with PT199, unlike with some other CD73 inhibitors in clinical development. Hence, PT199 addresses the limitations of current CD73 inhibitors and is expected to increase antitumor immune activation, especially in combination with PD-1 pathway inhibition, and thus offers a new treatment option for cancer patients. Methods This study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT199 alone and in combination with a PD-1 inhibitor, in patients with locally advanced or metastatic solid tumors that have progressed after all available standard therapy or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Approximately 32-38 patients will be enrolled. The study consists of 3 parts: Monotherapy Dose Escalation, Combination Therapy Dose Escalation, and Combination Dose Expansion. The dose escalation study of PT199 will be guided by a standard 3+3 dose escalation study design to determine the maximum tolerated dose (MTD) and/or the dose recommended for dose expansion (DRDE). The MTD and/or DRDE will be further evaluated in a dose expansion cohort and a recommended phase II dose (RP2D) may be determined based on the totality of the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy data obtained from both dose escalation and expansion cohorts. Each enrolled patient will receive PT199 as a monotherapy (10, 20, or 30 mg/kg QW) as an intravenous infusion continuously in 21-day cycles or in combination with a PD-1 inhibitor. Results The primary endpoints are Dose Limiting Toxicity and MTD, if reached, and RP2D of PT199 as a single agent and/or in combination with a PD-1 inhibitor. PD assessments will include measurements of CD73 enzyme activity and cytokines in serum and CD73/PD-L1 expression in tumor tissues. Conclusions The study is currently enrolling. Preliminary safety and efficacy data is anticipated the middle of next year. Trial Registration NCT05431270 Ethics Approval The study obtained ethics approval through a central IRB (Advara IRB: Pro00063442). All participants have given informed consent before taking part in this trial.

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin–angiotensin–aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg – a vasodilatory β1-selective antagonist/β3 agonist – and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I–II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Combining different classes of antihypertensives is more effective for reducing blood pressure (BP) than increasing the dose of monotherapies. The aims of this phase I study were to investigate pharmacokinetic and pharmacodynamic interactions between nebivolol, a vasodilatory β1-selective blocker, and valsartan, an angiotensin II receptor blocker, and to assess safety and tolerability of the combination. This was a single-center, randomized, open-label, multiple-dose, 3-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into 1 of 6 treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol (20 mg), valsartan (320 mg), and nebivolol-valsartan combination (20/320 mg). Outcomes included AUC0-τ,ss, Cmax,ss, Tmax,ss, changes in BP, pulse rate, plasma angiotensin II, plasma renin activity, 24-hour urinary aldosterone, and adverse events. Steady-state pharmacokinetic interactions were observed but deemed not clinically significant. Systolic and diastolic BP reduction was significantly greater with nebivolol-valsartan combination than with either monotherapy. The mean pulse rate associated with nebivolol and nebivolol-valsartan treatments was consistently lower than that associated with valsartan monotherapy. A sharp increase in mean day 7 plasma renin activity and plasma angiotensin II that occurred in valsartan-treated participants was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at day 7 was substantially decreased after combined treatment, as compared with either monotherapy. All treatments were safe and well tolerated. In conclusion, nebivolol and valsartan coadministration led to greater reductions in BP compared with either monotherapy; nebivolol and valsartan lower BP through complementary mechanisms.

Background: Combining different classes of antihypertensive drugs is more effective for achieving blood pressure (BP) control than increasing the dose of monotherapies. An aim of this study was to investigate pharmacodynamic (PD) interactions between nebivolol, a β1 selective, vasodilatory beta blocker and valsartan, an angiotensin II type 1 receptor blocker. Methods: This was a single-center, randomized, open-label, multiple-dose, three-way crossover trial in 30 healthy adults aged 18-45 years. Participants were randomized into one of six treatment sequences (1:1:1:1:1:1) consisting of three 7-day treatment periods followed by a 7-day washout. Once-daily oral treatments comprised nebivolol 20 mg, valsartan 320 mg, or nebivolol 20 mg plus valsartan 320 mg. Outcomes included changes in BP, heart rate (HR), plasma angiotensin II, plasma renin activity (PRA), and 24-hour urinary aldosterone. Results: The drop in least square mean values of systolic and diastolic BP was significantly greater following the concomitant administration of nebivolol and valsartan than either monotherapy alone. The mean HR after treatment with nebivolol alone, as well as after the combined treatment, was consistently lower than valsartan monotherapy. A sharp increase in mean Day 7 PRA and plasma angiotensin II occurred in subjects receiving valsartan alone and this was significantly attenuated with concomitant nebivolol administration. Mean 24-hour urine aldosterone at Day 7 was substantially decreased after combined treatment, as compared to either monotherapy treatment. All treatments were safe and well tolerated. Conclusion: Nebivolol and valsartan co-administration led to greater reductions in BP compared to either monotherapy. Nebivolol attenuated valsartan-induced increases in angiotensin II levels and PRA and reduced urinary aldosterone levels. Hence, these mechanisms for BP lowering are complementary and provide a rationale for further investigation of this combination in patients with essential hypertension.

Introduction The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase [PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treating hypertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats. Aim To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated. Methods HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil, tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA. Main Outcome Measures Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation of HPRA and cGMP accumulation in HCC. Results Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levels in HCC from DMED. Conclusions Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with diabetes.

Nebivolol is a selective β1 adrenergic receptor antagonist with nitric oxide-mediated vasodilatory properties utilized in the treatment of hypertension. Previously, nebivolol was shown to modulate amyloid-β protein precursor processing in vitro. In this study, we investigated the in vivo effects of nebivolol on the modulation of amyloid neuropathology in the Tg2576 mouse model of Alzheimer's disease (AD). We found that nebivolol is brain bioavailable and can be readily detected in the brain following three weeks of treatment at a dose of 1 mg/kg/day. Moreover, this treatment regime resulted in a significant reduction of amyloid-β neuropathology in the brain, and this reduction was inversely correlated with plasma levels of amyloid-β. Chronic nebivolol treatment of Tg2576 mice with established amyloid neuropathology and cognitive impairments significantly reduced brain amyloid content but failed to improve cognitive function. Our study demonstrates that nebivolol is highly tolerable and safe and can significantly reduce amyloid neuropathology in the brain, which could be one of the most important parameters for primary prevention of AD. Our studies support the continued investigation of nebivolol for the treatment of AD at very early stages of the disease.

Background: Erectile dysfunction (ED) is highly prevalent among diabetic men. In addition, diabetes is associated with a poorer therapeutic response to conventional therapy for ED, i.e. type 5 phos...

Objectives This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction.Background Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bio-availability. We hypothesized that specific beta(3)-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability.Methods Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 mu g/kg), BRL-37344 (1 mu g/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels.Results Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 +/- 4 ng/ml to 25 +/- 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta(3)-AR(-/-), eNOS(-/-), and in nNOS(-/-) mice.Conclusions Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability. (J Am Coll Cardiol 2011;58:2683-91) (C) 2011 by the American College of Cardiology Foundation

Nebivolol is a selective β1 adrenergic receptor antagonist with nitric oxide-mediated vasodilatory properties utilized in the treatment of hypertension. In a short-term feasibility study, seven months old Tg2576 Alzheimer's disease (AD) mice were treated orally for six weeks with 1 mg/kg/day of nebivolol. Brain and plasma Aβ contents were measured. In parallel bioavailability studies, brain and plasma contents of nebivolol were also measured. We found nebivolol treatment significantly reduced β-amyloid (Aβ) neuropathology in the brain. We found a significant inverse correlation between the contents of Aβ1-42 and Aβ1-40 peptides in the brain and in plasma. Moreover, we found no detectable change in amyloid precursor protein processing following nebivolol treatment. Collectively, our evidence suggests nebivolol treatment may promote Aβ clearance from the brain, in part by increasing efflux of Aβ peptides across the blood brain barrier into the peripheral circulation. In bioavailability studies nebivolol reached brain concentrations of ˜30 nM in mice with 1mg/kg/day treatment. No detectable changes in blood pressure or heart rate were detected under this treatment regimen. Our studies for the first time demonstrate that nebivolol, a highly tolerable, safe and selective β1 adrenergic receptor antagonist significantly promotes clearance of amyloidogenic Aβ peptides from the brain in the Tg2576 mice without any detectable changes in hemodynamics. Future studies will focus on the functional ability of nebivolol to attenuate AD-type cognitive deterioration in Tg2576 mice.

INTRODUCTION:Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β(1)-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism.AIM:We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues.METHODS:Erectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined.MAIN OUTCOME MEASURES:The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses.RESULTS:Treatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals.CONCLUSIONS:Nebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes.

Background: The B3-adrenergic receptor (B3-AR), found in the endothelium and myocardium, has emerged as a potential target for the treatment of cardiovascular diseases including hypertension, acute...

Preclinical Models/experimental hypertension P-268 the rOle OF the nitriC OXiDe/CyCliC GuanOSine MOnOPhOSPhate PathWay in the antihyPertenSiVe eFFeCtS OF the CarDiOSeleCtiVe, VaSODilatOry β1-BlOCKer, neBiVOlOl Javier Angulo1, Rocío González-Corrochano1, Argentina Fernández1, Harold M. Wright2, Sandeep Gupta2, Iñigo Sáenz de Tejada1. 1Dpto de Investigación, Investigacion y Clinica Andrologicas and Instituto de Medicina Sexual, Madrid, Spain; 2Dept. of Pharmacology, Forest Research Institute, Jersey City, NJ.

You have accessJournal of Urology1 Apr 2008NEBIVOLOL, A CARDIOSELECTIVE AND VASODILATORY B1-BLOCKER, ACTIVATES THE NITRIC OXIDE/CYCLIC GUANOSINE MONOPHOSPHATE PATHWAY, DILATES HUMAN PENILE ARTERIES AND ENHANCES ERECTILE FUNCTION IN RATS Javier Angulo, Rocio Gonzalez-Corrochano, Argentina Fernandez, Harold Wright, Sandeep Gupta, and Inigo Saenz de Tejada Javier AnguloJavier Angulo More articles by this author , Rocio Gonzalez-CorrochanoRocio Gonzalez-Corrochano More articles by this author , Argentina FernandezArgentina Fernandez More articles by this author , Harold WrightHarold Wright More articles by this author , Sandeep GuptaSandeep Gupta More articles by this author , and Inigo Saenz de TejadaInigo Saenz de Tejada More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(08)60807-1AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "NEBIVOLOL, A CARDIOSELECTIVE AND VASODILATORY B1-BLOCKER, ACTIVATES THE NITRIC OXIDE/CYCLIC GUANOSINE MONOPHOSPHATE PATHWAY, DILATES HUMAN PENILE ARTERIES AND ENHANCES ERECTILE FUNCTION IN RATS." The Journal of Urology, 179(4S), p. 278 © 2008 by American Urological AssociationFiguresReferencesRelatedDetails Volume 179Issue 4SApril 2008Page: 278 Advertisement Copyright & Permissions© 2008 by American Urological AssociationMetricsAuthor Information Javier Angulo More articles by this author Rocio Gonzalez-Corrochano More articles by this author Argentina Fernandez More articles by this author Harold Wright More articles by this author Sandeep Gupta More articles by this author Inigo Saenz de Tejada More articles by this author Expand All Advertisement PDF downloadLoading ...