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Objective: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure., Methods: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model., Results: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength., Interpretation: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva., Methods: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4., Results: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance., Conclusions: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety., Competing Interests: Declaration of competing interest At the time of writing, Dr. Bradley Messmer was CSO of Aegirbio AB and received stock compensation from Aegirbio AB. J. Foley has received research support from Biogen, Octave, and Genentech. He received speakers' honoraria from Biogen. He has participated in advisory boards for Biogen, Horizon, Sandoz, and TG Therapeutics. He is the founder of InterPro Biosciences. L.J.P, I.F.P, R.H, T.H and E.T.C report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential., Methods: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50)., Results: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower., Conclusion: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing., Competing Interests: Declaration of competing interest L.M.Y.G. had nothing to disclose. S.L. has nothing to disclose. A.A.T. has nothing to disclose. J.H. has nothing to disclose. F.C.L. has nothing to disclose. T.R. has received funding for research from Genmab; received consulting fees from Novartis. J.K. has received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trials of Immunic (payments to institution only). E.C.T. has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche and Novartis. Z.L.E.v.K. has nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Site-specific immunomodulators (SSIs) are a novel class of therapeutics made from inactivated bacterial species designed to regulate the innate immune system in targeted organs. QBECO is a gut-targeted SSI that is being advanced clinically to treat and/or prevent inflammatory bowel disease, cancer, and serious infections of the gastrointestinal (GI) tract and proximal organs, and QBKPN is a lung-targeted SSI that is in clinical development for the treatment and/or prevention of chronic inflammatory lung disease, lung cancers and respiratory tract infections. While these SSIs have demonstrated both safety and proof-of-concept in preclinical and clinical studies, detailed understanding of their trafficking and biodistribution is yet to be fully characterized., Methods: QBECO and QBKPN were radiolabeled with [ 89 Zr] and injected subcutaneously into healthy mice. The mice underwent Positron Emission Tomography (PET) imaging every day for eight days to track biodistribution of the SSIs. Tissue from the site of injection was collected and immunohistologically probed for immune cell infiltration., Results: Differential biodistribution of the two SSIs was seen, adhering to their site-specific targeting. QBKPN appeared to migrate from the site of injection (abdomen) to the cervical lymph nodes which are nearer to the respiratory tract and lungs. QBECO remained in the abdominal region, with lymphatic trafficking to the inguinal lymph nodes, which are nearer to GI-proximal tissues/organs. Immune infiltration at the site of injection comprised of neutrophils for both SSIs, and macrophages for only QBKPN., Conclusion: Radiolabeling of SSIs allows for longitudinal in vivo imaging of biodistribution and trafficking. PET imaging revealed differential biodistribution of the SSIs based on the organotropism of the bacteria from which the SSI is derived. Trafficking from the site of injection to the targeted site is in part mediated via the lymphatics and involves macrophages and neutrophils., Competing Interests: Declaration of competing interest SK is an employee of Qu Biologics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the safety, tolerability, pharmacokinetics, and efficacy of rituximab (RTX) in pediatric patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)., Methods: The Pediatric Polyangiitis Rituximab Study was a phase IIa, international, open-label, single-arm study. During the initial 6-month remission-induction phase, patients received intravenous infusions of RTX (375 mg/m 2 body surface area) and glucocorticoids once per week for 4 weeks. During the follow-up period, patients could receive further treatment, including RTX, for GPA or MPA. The safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy outcomes with RTX were evaluated., Results: Twenty-five pediatric patients with new-onset or relapsing disease were enrolled at 11 centers (19 with GPA [76%] and 6 with MPA [24%]). The median age was 14 years (range 6-17 years). All patients completed the remission-induction phase. During the overall study period (≤4.5 years), patients received between 4 and 28 infusions of RTX. All patients experienced ≥1 adverse event (AE), mostly grade 1 or grade 2 primarily infusion-related reactions. Seven patients experienced 10 serious AEs, and 17 patients experienced 31 infection-related AEs. No deaths were reported. RTX clearance correlated with body surface area. The body surface area-adjusted RTX dosing regimen resulted in similar exposure in both pediatric and adult patients with GPA or MPA. Remission, according to the Pediatric Vasculitis Activity Score, was achieved in 56%, 92%, and 100% of patients by months 6, 12, and 18, respectively., Conclusion: In pediatric patients with GPA or MPA, RTX is well tolerated and effective, with an overall safety profile comparable to that observed in adult patients with GPA or MPA who receive treatment with RTX. RTX is associated with a positive risk/benefit profile in pediatric patients with active GPA or MPA., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The pharmacokinetics of Ig20Gly, a 20% subcutaneous immunoglobulin (IG) therapy, is well characterized in IG-experienced patients with primary immunodeficiency diseases (PID). Data from IG-naïve patients are limited., Objective: Simulate serum total immunoglobulin G (IgG) pharmacokinetic profiles in IG-naïve patients with PID for different Ig20Gly initiation and maintenance dosing regimens., Methods: A population pharmacokinetic model developed with data from pivotal phase 2/3 trials of weekly Ig20Gly in PID (NCT01412385, NCT01218438) was used to simulate pharmacokinetic profiles of IgG in various scenarios with 400- or 800-mg/kg total loading doses (administered as split doses over 1-2 weeks) and corresponding 100- or 200-mg/kg weekly maintenance doses, respectively. Endogenous baseline IgG levels (1.5, 2.0, 4.0, 6.0 g/L) were evaluated for each scenario; time to putative therapeutic target IgG trough level (7 g/L) was determined., Results: Serum IgG levels reached steady-state by approximately Week 12 for all scenarios and baseline endogenous IgG levels. Time to target trough level generally occurred sooner with 1-week versus 2-week loading schemes. Endogenous baseline IgG levels <4 g/L required a 1-week 800-mg/kg total loading dose to achieve target levels within 2 weeks. Both maintenance regimens sustained serum IgG above target level., Conclusions: Simulations indicated IG-naïve patients with PID can achieve protective serum IgG levels within 1-3 weeks using appropriate Ig20Gly loading regimens. Patients with low endogenous IgG may benefit most from an 800-mg/kg/month loading dose. 400- or 800-mg/kg/month Ig20Gly maintenance regimens appeared adequate to maintain stable IgG levels. Serum IgG monitoring and clinical status can guide dosing parameters., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the independent contributions of clinical measures (relapses, Expanded Disability Status Scale [EDSS] scores, and neuroperformance measures) and nonclinical measures (new brain magnetic resonance imaging [MRI] activity and serum neurofilament light chain [sNfL] levels) for distinguishing natalizumab-treated from placebo-treated patients., Methods: We conducted post hoc analyses using data from the AFFIRM trial of natalizumab for multiple sclerosis. We used multivariable regression analyses with predictors (EDSS progression, no relapse, new or enlarging MRI activity, brain atrophy, sNfL levels, and neuroperformance worsening) to identify measures that independently discriminated between treatment groups., Results: The multivariable model that best distinguished natalizumab from placebo was no new or enlarging T2 or gadolinium-enhancing activity on MRI (odds ratio; 95% confidence interval: 7.2; 4.7-10.9), year 2 sNfL levels <97.5th percentile (4.1; 2.6-6.2), and no relapses in years 0-2 (2.1; 1.5-3.0). The next best-fitting model was a two-component model that included no MRI activity and sNfL levels <97.5th percentile at year 2. There was little difference between the three- and two-component models., Interpretation: Nonclinical measures (new MRI activity and sNfL levels) discriminate between treatment and placebo groups similarly to or better than clinical outcomes composites and have implications for patient monitoring., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The outbreak of mysterious pneumonia at the end of 2019 is associated with widespread research interest worldwide. The coronavirus disease-19 (COVID-19) targets multiple organs through inflammatory, immune, and redox mechanisms, and no effective drug for its prophylaxis or treatment has been identified until now. The use of dietary bioactive compounds, such as phenolic compounds (PC), has emerged as a putative nutritional or therapeutic adjunct approach for COVID-19. In the present study, scientific data on the mechanisms underlying the bioactivity of PC and their usefulness in COVID-19 mitigation are reviewed. In addition, antioxidant, antiviral, anti-inflammatory, and immunomodulatory effects of dietary PC are studied. Moreover, the implications of digestion on the putative benefits of dietary PC against COVID-19 are presented by addressing the bioavailability and biotransformation of PC by the gut microbiota. Lastly, safety issues and possible drug interactions of PC and their implications in COVID-19 therapeutics are discussed., (Copyright © 2021. Published by Elsevier Inc.)

Rituximab is a chimeric monoclonal antibody capable of depleting B cell populations by targeting the CD20 antigen expressed on the cell surface. Its use in oncology, initially in B cell lymphoma and post-transplant lymphoproliferative disorders, predates its current utility in various fields of medicine wherein it has become one of the safest and most effective antibody-based therapies. It was subsequently found to be effective for rheumatological conditions such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis. Over the past decade, rituximab has generated a lot of interest in nephrology and has become an emerging or accepted therapy for multiple renal conditions, including systemic lupus erythematosus, lupus nephritis, vasculitis, nephrotic syndrome and in different scenarios before and after kidney transplantation. This review outlines its current use in paediatric nephrology practice, focusing on the knowledge required for general paediatricians who may be caring for children prescribed this medication and reviewing them on a shared care basis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The atypical chemokine receptor C-X-C chemokine receptor type 7 (CXCR7) is an attractive therapeutic target for a variety of cardiac and immunological diseases. As a strategy to mitigate known risks associated with the development of higher molecular weight, basic compounds, a series of pyrrolidinyl-azolopyrazines were identified as promising small-molecule CXCR7 modulators. Using a highly enabled parallel medicinal chemistry strategy, structure-activity relationship studies geared towards a reduction in lipophilicity and incorporation of saturated heterocycles led to the identification of representative tool compound 20. Notably, compound 20 maintained good potency against CXCR7 with a suitable balance of physicochemical properties to support in vivo pharmacokinetic studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Objectives: Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS)., Methods: This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations., Results: Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment., Discussion: Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 + T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS., Classification of Evidence: This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Astaxanthin (AST) is a red pigment of carotenoid and is considered a high-quality keto-carotenoid pigment with food, livestock, cosmetic, therapeutic and nutraceutical proposes. Astaxanthin exists naturally in fish, crustacean, algae, and birds that naturally exists, principally as fatty acid esters. Many investigations have exhibited the beneficial impacts of astaxanthin when utilized as a pharmaceutical agent in animal nutrition. Astaxanthin has a variety of considerable biological actions, such as being antihypertensive, an antioxidant, anti-obesity properties, and anti-carcinogenic. Astaxanthin has recently acquired popularity as a powerful immunomodulator to maintain the health status and well-being of both animals and humans. The use of astaxanthin is broadly utilized in medical sciences and the nutrition pf aquatic species; however, it presently has limited applications in broader animal nutrition. Understanding astaxanthin's structure, source, and mode of action in the body provides a conceptual base for its clinical application and could enhance the screening of compounds associated with the treatment of many diseases. This review article aims to clarify the important aspects of astaxanthin such as its synthesis, bioavailability, and therapeutics actions, with special interest in practical applications. Awareness of this benefits and production is expected to aid the livestock industry to develop nutritional strategies that ensure the protection of animal health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Safe and effective new oral therapies for autoimmune, allergic, and inflammatory conditions remain a significant therapeutic need. Here, we investigate the human pharmacokinetics, pharmacodynamics (PDs), and safety of the selective, covalent Bruton's tyrosine kinase (BTK) inhibitor, remibrutinib. Study objectives were explored in randomized single and multiple ascending dose (SAD and MAD, respectively) cohorts with daily doses up to 600 mg, and a crossover food effect (FE) cohort, in adult healthy subjects without (SAD [n =80]/FE [n =12]) or with asymptomatic atopic diathesis (MAD [n =64]). A single oral dose of remibrutinib (0.5-600 mg) was rapidly absorbed (time to maximum concentration = 0.5 h-1.25 h) with an apparent blood clearance of 280-560 L/h and apparent volume of distribution of 400-15,000 L. With multiple doses (q.d. and b.i.d.), no pronounced accumulation of remibrutinib was detected (mean residence time was <3 h). Food intake showed no clinically relevant effect on remibrutinib exposure suggesting no need for dose adaptation. With remibrutinib doses greater than or equal to 30 mg, blood BTK occupancy was greater than 95% for at least 24 h (SAD). With MAD, remibrutinib reached near complete blood BTK occupancy at day 12 predose with greater than or equal to 10 mg q.d. Near complete basophil or skin prick test (SPT) inhibition at day 12 predose was achieved at greater than or equal to 50 mg q.d. for CD63 and at greater than or equal to 100 mg q.d. for SPT. Remibrutinib was well-tolerated at all doses without any dose-limiting toxicity. Remibrutinib showed encouraging blood and skin PDs with a favorable safety profile, supporting further development for diseases driven by mast cells, basophils, and B-cells, such as chronic spontaneous urticaria, allergic asthma, or Sjögren's syndrome., (© 2021 Novartis Institutes for BioMedical Research. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objective: To determine the transfer of the monoclonal antibody natalizumab into breastmilk and to evaluate drug and serum neurofilament light chain ((s)NfL) levels in natalizumab exposed pregnancies and lactation periods., Methods: Eleven women with relapsing remitting multiple sclerosis treated with natalizumab during pregnancy and lactation were included in this study. Breastmilk samples were collected up to 302 days after delivery and analyzed for natalizumab concentration and NfL. Additionally, maternal drug levels and sNfL were determined preconceptually, in each trimester, at delivery and postpartum. Clinical and radiological disease activity was systemically assessed across pregnancy and postpartum period., Results: The mean average natalizumab concentration in breast milk was low at 0.06 µg/ml [standard deviation (SD) 0.05] in the eight patients who provided serial breastmilk samples with an estimated mean absolute infant dose of 0.007 mg/kg/d (SD 0.005). The relative infant dose (RID), a metric comparing the infant with maternal drug exposure was low as well with a mean of 0.04% (SD=0.03). Most patients had a maximum concentration in breast milk at one to eight days after infusion. Pregnancy was associated with a non-significant decline of the median natalizumab serum concentration. All patients exposed to natalizumab prior (n=10) and during pregnancy (n=11) kept free of disease activity during gestation. While pregnancy was associated with low sNfL levels in patients treated with natalizumab prior and during pregnancy, the postpartum period was linked to a transient sNfL increase in some patients without any evidence of clinical or radiological disease activity. NfL was detectable in the majority of breastmilk samples with a median concentration of 1.7 pg/ml (range 0.004-18.1)., Conclusion: We determined transfer of natalizumab into breastmilk with an RID far below the threshold of concern of 10%. Studies including childhood development assessment are needed in order to gain safety data about natalizumab-exposed breastfeeding. SNfL assessment might be a useful adjunct to monitor silent disease activity and therapeutic response during pregnancy and postpartum period. However, further investigations regarding transient postpartum sNfL increases are required to determine its association to parturition per se or to a silent disease activity in people with multiple sclerosis., Competing Interests: UP received speaker fee from Merck, Biogen and Bayer and personal compensation from Biogen and Roche for consulting service. RH has received travel compensation from Celgene and Sanofi. HI received speaker fee from Roche. KA received personal compensation from Roche, Sanofi, Alexion, Teva, Biogen and Celegene for consulting service. TZ reports consulting or serving at speaker bureaus for Biogen, Celgene, Roche, Novartis, Celgene, Merck and Sanofi as well as research support from Biogen, Novartis, Merck and Sanofi., (Copyright © 2021 Proschmann, Haase, Inojosa, Akgün and Ziemssen.)

The two main objectives of this analysis were to (i) characterize the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra ® ) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG pharmacokinetic (PK) parameters, including those from a previous population PK model, were used to predict individual IgG profile and exposure metrics. Treatment-related changes in Inflammatory Neuropathy Cause and Treatment (INCAT) scores were best described by a maximum effect (E max ) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilization). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose., (© 2021 CSL Behring. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

RO6870868 is an oral prodrug of the toll-like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first-in-human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200-2000 mg). Single oral doses were generally well-tolerated with a predictable safety profile associated with dose-dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half-life ranging 2-6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC 0-∞ ) increasing proportionally with dose. A pattern of dose and time-dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose-dependent manner with adequate safety and tolerability. Single-dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B., (© 2021 Deep Dives in Pharma Research, LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The Coronavirus disease (COVID-19) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagious disease. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific antivirals and immunomodulators. Ayurvedic Rasayana therapy has been traditionally used in India for its immunomodulatory and adaptogenic effects, and more recently has been included as therapeutic adjuvant for several maladies. Amongst several others, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) play an important role in Rasayana therapy. The objective of this study was to explore the immunomodulatory and anti SARS-CoV2 potential of phytoconstituents from Ashwagandha, Guduchi and Shatavari using network pharmacology and docking. The plant extracts were prepared as per ayurvedic procedures and a total of 31 phytoconstituents were identified using UHPLC-PDA and mass spectrometry studies. To assess the immunomodulatory potential of these phytoconstituents an in-silico network pharmacology model was constructed. The model predicts that the phytoconstituents possess the potential to modulate several targets in immune pathways potentially providing a protective role. To explore if these phytoconstituents also possess antiviral activity, docking was performed with the Spike protein, Main Protease and RNA dependent RNA polymerase of the virus. Interestingly, several phytoconstituents are predicted to possess good affinity for the three targets, suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would not be adverse herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals as therapeutic adjuvants in the management of COVID-19 following rigorous experimental validation., Competing Interests: Authors (AG and LH) are affiliated with Pharmanza Herbals Pvt. Ltd. The herbal extracts used in the study are a marketed product of Pharmanza Herbals Pvt. Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction : Women with inflammatory bowel disease (IBD) endorse a tremendous amount of concern about medication exposure during pregnancy and their effects on the fetus. Medical providers caring for this patient population should be well informed and feel comfortable counseling their patients for the best pregnancy outcome possible. Areas covered : It is of particular importance to understand the implications of use of biologics in preconception, pregnancy, and postpartum timeframes. Herein, we aim to inform the clinician about the impact of uncontrolled inflammation during pregnancy, the mechanisms of biologic transport through the placenta, the effects of biologics in maternal and neonatal outcomes, and additional postpartum considerations such as breastfeeding and vaccination safety. Expert opinion : The groundwork already set by previous research in terms of safety of biologic therapy during pregnancy has been reassuring. With the advent of more mechanisms of action but similar protein structure, i.e. they are IgG1 antibodies; the authors anticipate the recommendation of continuation of therapy throughout pregnancy will be sustained.

Background: Published reports on tocilizumab in COVID-19 pneumonitis show conflicting results due to weak designs or heterogeneity in critical methodological issues., Methods: This open-label trial, structured according to Simon's optimal design, aims to identify factors predicting which patients could benefit from anti-IL6 strategies and to enhance the design of unequivocal and reliable future randomized trials. A total of 46 patients with COVID-19 pneumonia needing of oxygen therapy to maintain SO2 > 93% and with recent worsening of lung function received a single infusion of tocilizumab. Clinical and biological markers were measured to test their predictive values. Primary end point was early and sustained clinical response., Results: Twenty-one patients fulfilled pre-defined response criteria. Lower levels of IL-6 at 24 h after tocilizumab infusion (P = 0.049) and higher baseline values of PaO2/FiO2 (P = 0.008) predicted a favourable response., Conclusions: Objective clinical response rate overcame the pre-defined threshold of 30%. Efficacy of tocilizumab to improve respiratory function in patients selected according to our inclusion criteria warrants investigations in randomized trials., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)

Understanding individual responses to nutrition and medicine is of growing interest and importance. There is evidence that differences in bitter taste receptor (TAS2R) genes which give rise to two frequent haplotypes, TAS2R38-PAV (functional) and TAS2R38-AVI (non-functional), may impact inter-individual differences in health status. We here analyzed the relevance of the TAS2R38 receptor in the regulation of the human immune response using the TAS2R38 agonist allyl isothiocyanate (AITC) from Brassica plants. A differential response in calcium mobilization upon AITC treatment in leucocytes from healthy humans confirmed a relevance of TAS2R38 functionality, independent from cation channel TRPV1 or TRPA1 activation. We further identified a TAS2R38-dependence of MAPK and AKT signaling activity, bactericidal (toxicity against E. coli ) and anti-inflammatory activity (TNF-alpha inhibition upon cell stimulation). These in vitro results were derived at relevant human plasma levels in the low micro molar range as shown here in a human intervention trial with AITC-containing food., Competing Interests: A part of the study was financed by a grant from Repha gmbh, Langenhagen, Germany. Repha GmbH was not involved in the study design, interpretation of the results or writing of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Tran, Stetter, Herz, Spöttel, Krell, Hanschen, Schreiner, Rohn, Behrens and Lamy.)

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt's lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89 Zr/ 177 Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management., Competing Interests: Weibo Cai is scientific advisor, stockholder, and grantee of Focus‐X Therapeutics, Inc. The other authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Over 50 million people have been infected with the SARS-CoV-2 virus, while around 1 million have died due to COVID-19 disease progression. COVID-19 presents flu-like symptoms that can escalate, in about 7-10 days from onset, into a cytokine storm causing respiratory failure and death. Although social distancing reduces transmissibility, COVID-19 vaccines and therapeutics are essential to regain socioeconomic normalcy. Even if effective and safe vaccines are found, pharmacological interventions are still needed to limit disease severity and mortality. Integrating current knowledge and drug candidates (approved drugs for repositioning among >35 candidates) undergoing clinical studies (>3000 registered in ClinicalTrials.gov), we employed Systems Pharmacology approaches to project how antivirals and immunoregulatory agents could be optimally evaluated for use. Antivirals are likely to be effective only at the early stage of infection, soon after exposure and before hospitalization, while immunomodulatory agents should be effective in the later-stage cytokine storm. As current antiviral candidates are administered in hospitals over 5-7 days, a long-acting combination that targets multiple SARS-CoV-2 lifecycle steps may provide a long-lasting, single-dose treatment in outpatient settings. Long-acting therapeutics may still be needed even when vaccines become available as vaccines are likely to be approved based on a 50% efficacy target., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Dihydrochalcones, phlorizin (PZ) and its aglycone phloretin (PT), have evidenced immunomodulatory effects through several mechanisms. However, the differential metabolic signatures that lead to these properties are largely unknown. Since macrophages play an important role in the immune response, our study aimed to characterise human THP-1 macrophages under PZ and PT exposure. A multiplatform-based untargeted metabolomics approach was used to reveal metabolites associated with the anti-inflammatory mechanisms triggered by the dihydrochalcones in LPS-stimulated macrophages, for the first time. Results showed differential phenotypic response in macrophages for all treatments. Dihydrochalcone treatment in LPS-stimulated macrophages mimics the response under normal conditions, suggesting inhibition of LPS response. Antagonistic effects of dihydrochalcones against LPS was mainly observed in glycerophospholipid and sphingolipid metabolism besides promoting amino acid biosynthesis. Moreover, PT showed greater metabolic activity than PZ. Overall, the findings of this study yielded knowledge about the mechanisms of action PZ and PT at metabolic level in modulating inflammatory response in human cells.

Purpose: Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects., Methods: A total of 33 males and 5 females with 19 subjects per part were enrolled. Part 1 evaluated the pharmacokinetics (PK) of iberdomide alone (0.6 mg) and when administered with the CYP3A and P-gp inhibitor itraconazole (200 mg twice daily on day 1 and 200 once daily on days 2 through 9). Part 2 evaluated the PK of iberdomide alone (0.6 mg) and with CYP3A4 inducer rifampin (600 mg QD days 1 through 13). Plasma concentrations of iberdomide and the active metabolite M12 were determined by validated liquid chromatography-tandem mass spectrometry assay., Results: Coadministration of iberdomide with itraconazole increased iberdomide peak plasma concentration (C max ) 17% and area under the concentration curve (AUC) approximately 2.4-fold relative to administration of iberdomide alone. The C max and AUC of iberdomide were reduced by approximately 70% and 82%, respectively, when iberdomide was administered with rifampin compared with iberdomide administered alone. Exploratory assessment of metabolite M12 concentrations demonstrated that CYP3A is responsible for M12 formation., Conclusions: Caution should be taken when coadministering iberdomide with strong CYP3A inhibitors. Coadministration of iberdomide with strong CYP3A inducers is not advised., Clinical Trial Registration: Clinical trial identification number is NCT02820935 and was registered in July 2016.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that results in severe inflammatory microenvironments in the joint tissues. In clinics, disease-modifying antirheumatic drugs (DMARDs) are generally prescribed to patients with RA, but their long-term use often shows toxicity in some organs such as the gastrointestinal system, skin, and kidneys and immunosuppression-mediated infection. Nanomedicine has emerged as a new therapeutic strategy to efficiently localize the drugs in inflamed joints for the treatment of RA. In this Review, we introduce recent research in the area of nanomedicine for the treatment of RA and discuss how the nanomedicine can be used to deliver therapeutic agents to the inflamed joints and manage the progression of RA, particularly focusing on targeted delivery, controlled drug release, and immune modulation.

Licorice extract is a Chinese herbal medication most often used as a demulcent or elixir. The extract usually consists of many components but the key ingredients are glycyrrhizic (GL) and glycyrrhetinic acid (GA). GL and GA function as potent antioxidants, anti-inflammatory, antiviral, antitumor agents, and immuneregulators. GL and GA have potent activities against hepatitis A, B, and C viruses, human immunodeficiency virus type 1, vesicular stomatitis virus, herpes simplex virus, influenza A, severe acute respiratory syndrome-related coronavirus, respiratory syncytial virus, vaccinia virus, and arboviruses. Also, GA was observed to be of therapeutic valve in human enterovirus 71, which was recognized as the utmost regular virus responsible for hand, foot, and mouth disease. The anti-inflammatory mechanism of GL and GA is realized via cytokines like interferon- γ , tumor necrotizing factor- α , interleukin- (IL-) 1 β , IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-17. They also modulate anti-inflammatory mechanisms like intercellular cell adhesion molecule 1 and P-selectin, enzymes like inducible nitric oxide synthase (iNOS), and transcription factors such as nuclear factor-kappa B, signal transducer and activator of transcription- (STAT-) 3, and STAT-6. Furthermore, DCs treated with GL were capable of influencing T-cell differentiation toward Th1 subset. Moreover, GA is capable of blocking prostaglandin-E2 synthesis via blockade of cyclooxygenase- (COX-) 2 resulting in concurrent augmentation nitric oxide production through the enhancement of iNOS2 mRNA secretion in Leishmania-infected macrophages. GA is capable of inhibiting toll-like receptors as well as high-mobility group box 1., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Seidu A. Richard.)

The importance of pharmacokinetic (PK) evaluation in pediatric drug development is well recognized, and a pediatric PK study is generally recommended before pivotal trials to ensure the "right" dose in these studies. The PK of therapeutic monoclonal antibodies (mAbs) is primarily affected by body weight, where adults-to-children extrapolation may conform to allometry. Therefore, PK behavior of mAbs in pediatrics, particularly for those with linear PK, is expected to be predictable based on data in adults. To test this hypothesis, we reviewed published population PK reports of marketed mAbs and assessed model-aided PK extrapolation of mAbs to children (2-17 years) through 5 case studies. For each case study, population PK models were developed based on adult data, with allometric exponents of weight on clearance and volume of distribution fixed as standard values (ie, 0.75 for clearance; 1.0 for volume of distribution), approach 1, or coming from adult model estimates, approach 2. Simulated pediatric PK using these 2 approaches was compared with PK observations in pediatric trials to assess the accuracy in model predictions. For pediatrics 6-17 years, model performance was generally comparable with the 2 approaches. For children < 6 years, no definite conclusion could be made, as only 1 case study enrolled children 2-5 years. Our work supports that PK in children 6-17 years is readily predictable for mAbs with linear PK based on adult data and considering weight effect (allometry). Empirical dosing calculations based on PK simulations with allometry are proposed to convert adult doses to equivalent pediatric doses with exposure matching for mAbs in children 2-17 years., (© 2020, The American College of Clinical Pharmacology.)

We describe outcomes from the first-in-human study of garetosmab (a fully human monoclonal antibody that inhibits activin A) under development for the treatment of fibrodysplasia ossificans progressiva (FOP). In a double-blind, placebo-controlled phase 1 study, 40 healthy women of nonchildbearing potential were randomized to receive a single dose of intravenous garetosmab 0.3, 1, 3, or 10 mg/kg; subcutaneous garetosmab 300 mg; or placebo. Serum concentrations of functional garetosmab (with ≥1 arm free to bind to target), total activin A, and antidrug antibodies were measured predose and up to 113 days post-first dose. Garetosmab demonstrated an acceptable safety profile with no dose-limiting toxicities. Garetosmab displayed nonlinear pharmacokinetics with target-mediated elimination. With increasing doses of intravenous garetosmab, mean peak concentration increased in a dose-proportional manner; mean steady-state estimates ranged from 41.4 to 47.8 mL/kg. A greater than dose-proportional increase in mean area under the concentration-time curve from time zero extrapolated to infinity (range, 72.2-7520 mg*day/L) was observed, consistent with decreasing mean clearance (range, 4.35-1.34 mL/day/kg). Following administration of intravenous garetosmab, mean concentrations of total activin A increased in a dose-dependent manner. At 10 mg/kg, total activin A levels reached a state of little or no change between weeks 4 and 12, suggesting saturation of the target-mediated pathway. No safety signals were seen in this study to preclude investigation in patients. Following intravenous administration, garetosmab concentrations decreased quickly, then decreased over time (reflecting linear elimination), and finally decreased in a nonlinear phase, reflecting target-mediated elimination. Results here support further investigation. Garetosmab 10 mg/kg every 4 weeks intravenously is being evaluated in patients with FOP (NCT03188666)., (© 2020 Regeneron Pharmaceuticals, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Total glycoside of paeony (TGP) has been widely used to treat inflammation and immune diseases in China. Paeoniflorin (Pae) is the major active component of TGP. Although TGP has few adverse drug reactions, the slow onset and low bioavailability of Pae limit its clinical use. Enhanced efficacy without increased toxicity is pursued in developing new agents for inflammation and immune diseases. As a result, paeoniflorin-6'-O-benzene sulfonate (CP-25) derived from Pae, is developed in our group, and exhibits superior bioavailability and efficacy than Pae. Here we describe the development process and research advance on CP-25. The pharmacokinetic parameters of CP-25 and Pae were compared in vivo and in vitro. CP-25 was also compared with the first-line drugs methotrexate, leflunomide, and hydroxychloroquine in their efficacy and adverse effects in arthritis animal models and experimental Sjögren's syndrome. We summarize the regulatory effects of CP-25 on inflammation and immune-related cells, elucidate the possible mechanisms, and analyze the therapeutic prospects of CP-25 in inflammation and immune diseases, as well as the diseases related to its potential target G-protein-coupled receptor kinases 2 (GRK2). This review suggests that CP-25 is a promising agent in the treatment of inflammation and immune diseases, which requires extensive investigation in the future. Meanwhile, this review provides new ideas about the development of anti-inflammatory immune drugs.

Polyphenols have demonstrated several potential biological activities, notably antitumoral activity dependent on immune function. In the present review, we describe studies that investigated antitumor immune responses influenced by polyphenols and the mechanisms by which polyphenols improve the immune response. We also discuss the limitations in related areas, especially unexplored areas of research, and next steps required to develop a therapeutic approach utilizing polyphenols in oncology., (Copyright © 2020. Published by Elsevier Inc.)

Due to frequent drug resistance and/or unwanted side-effects during conventional and targeted cancer treatments, development of multi-target therapies is an important research field. Medicinal mushrooms' isolated specific compounds and mushroom extracts have been already proven as non-toxic multi-target inhibitors of specific oncogenic pathways, as well as potent immunomodulators. However, research on antitumor effects of multiple-species extract mixtures was limited so far. The aim of this study was therefore, a study of medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS on colorectal cell lines in vitro and colorectal mice model in vivo. We found a significant antiproliferative and pro-apoptotic effect of tested medicinal mushroom preparations on colorectal (HCT-116, SW620) tumor cell lines, while the effect on human fibroblast cell line (WI-38) was proliferative emphasizing a specificity towards tumor cell lines. We further investigated the effect of the medicinal mushroom preparations AGARIKON.1 and AGARIKON PLUS in various combinations with conventional cytostatic drug 5-fluorouracil in the advanced metastatic colorectal cancer mouse model CT26.WT. AGARIKON.1 and AGARIKON PLUS exhibited immunostimulatory and antiangiogenic properties in vivo which resulted in significantly increased survival and reduction in tumor volume. The antitumor effects of AGARIKON.1 and AGARIKON PLUS, with or without 5-fluorouracil, are based on M1 macrophage polarization enhancement, inhibition of M2 and tumor-associated macrophage (TAM) polarization, effects on T helper cell Th1/Th2/Th17 cytokine profiles, direct inhibition of CT26.WT tumor growth, inhibition of vascular endothelial growth factors (VEGF) and metalloproteinases 2 and 9 (MMP-2 and MMP-9) modulation. The administration of AGARIKON.1 and AGARIKON PLUS did not show genotoxic effect. This data provides good basis for an expanded translational study.

Increasing pharmacological evidence supports that paeoniflorin, a water-soluble monoterpene glycoside isolated from Paeonia lactiflora Pall. (Shaoyao in Chinese), has a wide range of medicinal properties including anti-inflammatory, antioxidant, antithrombotic, anticonvulsive, analgesic, cardioprotective, neuroprotective, hepatoprotective, antidepressant-like, antitumoral, and immune-regulatory activities; as well as enhancing cognition and attenuating learning impairment. In addition to pharmacodynamic studies, information on pharmacokinetics is also significant for the further development and utilization of paeoniflorin. The present review focuses on the absorption, distribution, metabolism, and excretion of paeoniflorin, especially main pharmacological activities of paeoniflorin on inflammation and immune function. According to the findings obtained both in vitro and in vivo, a broad application prospect has been opened for paeoniflorin. However, further studies are needed to clarity the direct molecular mechanisms and key targets underlying the beneficial effects of paeoniflorin on inflammation and immunity., (Copyright © 2020. Published by Elsevier Masson SAS.)

Antibody-drug conjugates are important molecular entities in the treatment of cancer, with 8 antibody-drug conjugates approved by the US Food and Drug Administration since 2000 and many more in early- and late-stage clinical development. These conjugates combine the target specificity of monoclonal antibodies with the potent anticancer activity of small-molecule therapeutics. The complex structure of antibody-drug conjugates poses unique challenges to pharmacokinetic (PK) and pharmacodynamic (PD) characterization because it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (eg, conjugate, total antibody, and unconjugated payload) in different tissues. Quantitative clinical pharmacology using mathematical modeling and simulation provides an excellent approach to overcome these challenges, as it can simultaneously integrate the disposition, PK, and PD of antibody-drug conjugates and their components in a quantitative manner. In this review, we highlight diverse quantitative clinical pharmacology approaches, ranging from system models (eg, physiologically based pharmacokinetic [PBPK] modeling) to mechanistic and empirical models (eg, population PK/PD modeling for single or multiple analytes, exposure-response modeling, platform modeling by pooling data across multiple antibody-drug conjugates). The impact of these PBPK and PK/PD models to provide insights into clinical dosing justification and inform drug development decisions is also highlighted., (© 2020 Genentech, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Antibody therapeutics continue to represent a significant portion of the biotherapeutic pipeline, with growing promise for bispecific antibodies (BsAbs). BsAbs can target 2 different antigens at the same time, such as simultaneously binding tumor-cell receptors and recruiting cytotoxic immune cells. This simultaneous engagement of 2 targets can be potentially advantageous, as it may overcome disadvantages posed by a monotherapy approach, like the development of resistance to treatment. Combination therapy approaches that modulate 2 targets simultaneously offer similar advantages, but BsAbs are more efficient to develop. Unlike combination approaches, BsAbs can facilitate spatial proximity of targets that may be necessary to induce the desired effect. Successful development of BsAbs requires understanding antibody formatting and optimizing activity for both targets prior to clinical trials. To realize maximal efficacy, special attention is required to fully define pharmacokinetic (PK)/pharmacodynamic (PD) relationships enabling selection of dose and regimen. The application of physiologically based pharmacokinetics (PBPK) has been evolving to inform the development of novel treatment modalities such as bispecifics owing to the increase in our understanding of pharmacology, utility of multiscale models, and emerging clinical data. In this review, we discuss components of PBPK models to describe the PK characteristics of BsAbs and expand the discussion to integration of PBPK and PD models to inform development of BsAbs. A framework that can be adopted to build PBPK-PD models to inform the development of BsAbs is also proposed. We conclude with examples that highlight the application of PBPK-PD and share perspectives on future opportunities for this emerging quantitative tool., (© 2020, The American College of Clinical Pharmacology.)

The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5'-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 ( 35 ) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8 + T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

Interleukin-15 (IL-15) is crucial for the proliferation and survival of NK and CD8 + T memory cells, and of significant interest in immuno-oncology. Immune cell expansion requires continuous IL-15 exposure above a threshold concentration for an extended period. However, the short t 1/2 of IL-15 makes this impossible to achieve after a single injection without a high C max and toxicities. The most effective way to deliver IL-15 is continuous intra-venous infusion, but this administration mode is impractical. Efforts have been devoted to developing IL-15 agonists which after a single injection maintain the cytokine in a narrow therapeutic window for a long period. Enigmatically, although the half-life extension technologies used often extend the half-life of a protein to 1 or more weeks, the modified IL-15 agonists studied usually have systemic elimination half-lives of only a few hours and rarely much longer than 1 day. These short half-lives-common to all circulating IL-15 agonists thus far reported-can be explained by a dynamic increase in clearance of the agonists that accompanies target immune cell proliferation. What is needed is an IL-15 agonist that is as effective as continuous intravenous infusion, but with the convenience and acceptance of single injections at 1-week or longer intervals., (Copyright © 2020 Hangasky, Waldmann and Santi.)

Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on pomalidomide PK. Although body surface area was identified as a statistically significant covariate of pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4 mg of pomalidomide for the combination treatment. Finally, pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period., (© 2020, The American College of Clinical Pharmacology.)

Introduction: Ovarian cancer has only a 17% 5-year survival rate in patients diagnosed with late stage disease. Tumor-associated glycoprotein-72 (TAG72), expressed in 88% of all stages of ovarian cancer, is an excellent candidate for antibody-targeted therapy, as it is not expressed in normal human adult tissues, except in the secretory endometrium., Methods: Using the clinically relevant anti-TAG72 murine monoclonal antibody CC49, we evaluated antibody drug conjugates (ADCs) incorporating the highly potent, synthetic antimitotic agent monomethylauristatin E (MMAE). MMAE was conjugated to CC49 via reduced disulfides in the hinge region, using three different types of linker chemistry, vinylsulfone (VS-MMAE), bromoacetamido (Br-MMAE), and maleimido (mal-MMAE)., Results: The drug antibody ratios (DARs) of the three ADCs were 2.3 for VS-MMAE, 10 for Br-MMAE, and 9.5 for mal-MMAE. All three ADCs exhibited excellent tumor to blood ratios on PET imaging, but the absolute uptake of CC49-mal-MMAE (3.3%ID/g) was low compared to CC49-Br-MMAE (6.43%ID/g), at 142 hours. Blood clearance at 43 hours was 38% for intact CC49, about 24% for both CC49-VS-MMAE and CC49-Br-MMAE, and 7% for CC49-mal-MMAE. CC49-VS-MMAE was not further studied due to its low DAR, while CC49-mal-MMAE was ineffective in the OVCAR3 xenograft likely due to its rapid blood clearance. In contrast, CC49-Br-MMAE treated mice exhibited an average of a 15.6 day tumor growth delay and a 40% increase in survival vs controls with four doses of 7.5 or 15 mg/kg of CC49-Br-MMAE., Conclusion: We conclude that CC49-Br-MMAE with a high DAR and stable linker performs well in a difficult to treat solid tumor model., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The minimum effective dose of intramuscular polyvalent immune globulin for prevention of hepatitis A post-exposure is unknown. In Australia current dosing is according to weight category., Methods: The peak concentration and decay of hepatitis A antibodies after intramuscular dosing of immune globulin in adults was modeled utilizing published parameters. Models simulated dosing according to current Australian guidelines, then adjusted the dose in clinically relevant increments to estimate the optimal dose of hepatitis A antibodies for post-exposure prophylaxis of nonimmune individuals. Optimal dosing assumed a target serum concentration of hepatitis A antibodies of the correlate of protection plus a 10% margin of error at an incubation period. The effect of weight on hepatitis A antibody concentration at an incubation period under current guidelines was examined by fixing weight in 5 kg increments., Results: Current dosing guidelines in Australia may underdose people who weigh in excess of 85 kg. The optimal dose of hepatitis A-specific antibodies according to the model was 3.6, 2.5, and 1.9 IU/kg assuming 50%, 75% and 100% bioavailability respectively., Conclusions: For individuals in Australia recommended passive immunization as post-exposure prophylaxis and weighing in excess of 85 kg, conservative management would include dosing between 2.5 and 3.6 IU hepatitis A antibodies/kg.

Photodynamic therapy (PDT), as one of the most powerful photo-therapeutic strategies for cancer treatment with minimum invasiveness, can effectively damage local tumor cells and significantly induce systemic antitumor immunity. However, current nanotechnology-assisted PDT-immunomodulators have either poor penetration for deep tumors or low singlet oxygen generation. Herein, we construct a novel theranostic nanocarrier (HA-PEG-CyI, HPC) by inducing the self-assembly of PEGylated CyI and attaching the ligand HA to its surface. The prepared HPC can be used as an ideal PDT-immunomodulator for synergistic cancer therapy. CyI is an iodinated-cyanine dye with enhanced singlet oxygen generation ability as well as excellent photo-to-photothermal and near-infrared fluorescence imaging properties. Under 808 nm laser irradiation, the prepared HPC can generate both reactive oxygen species (ROS) and elevate temperature which can subsequently result in apoptosis and necrosis at tumor sites. Moreover, the HPC-induced cell death can generate a series of acute inflammatory reactions, leading to systemic immunity induction and secondary death of tumor cells, which further results in reducing tumor recurrence. In vitro and in vivo results show that HPC can enhance the tumor targeting efficacy, generate ROS efficiently and exhibit a high temperature response under NIR irradiation, which working together can activate immune responses for synergistic phototherapy on tumor cells. Accordingly, the proposed multi-functional HPC nanocarriers represent an important advance in PDT and can be used as a superior cancer treatment strategy with great promise for clinical applications.

Objective: To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases., Methods: We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and "breastmilk," "breast milk," "breastfeeding," or "lactation." From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women., Results: Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections., Conclusions: The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3+ cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3+ T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3+CD8+ T and CD8+IFN-γ+ T and the ratios of CD8+/Treg, and deceased the CD4+CD25+CD127low/- (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8+ T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound., Competing Interests: Luye Pharma provided the cell culture room for us to cultrue B16-F10 and CT26.WT tumor cells, and human CD3+ cells. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Immunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age)., Objective: The objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2-3 blood samples)., Method: Immunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis., Results: A non-compartmental analysis of IgG from neonates (bodyweight range 0.78-1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling., Conclusion: Our study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range., (Published by Elsevier B.V.)

Objective: We aimed to investigate whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes., Methods: In this cross-sectional study of 40 patients with relapsing-remitting MS (RRMS) receiving natalizumab at the Department of Neurology, Haukeland University Hospital, we recorded clinical and demographic data including age, body mass index (BMI), working status, smoking habits, disease characteristics, treatment duration, vitamin D levels, and wearing-off symptoms. We quantified neurofilament light chain in serum and measured natalizumab RO in leukocyte subtypes by high-parameter mass cytometry. Associations with wearing-off symptoms were analyzed., Results: Eight (20.0%) patients who reported regular occurrence of wearing-off symptoms, 9 (22.5%) who sometimes had wearing-off symptoms, and 23 (57.5%) who did not have wearing-off symptoms were evaluated. Patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon., Conclusions: Low RO may explain the wearing-off phenomenon observed in some patients with RRMS treated with natalizumab, and high BMI may be the underlying cause., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ., Methods: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α 4 -integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints., Results: Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ., Conclusions: Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Therapeutic monoclonal antibodies (mAbs) are increasingly used to treat a variety of conditions. The sources of their interindividual pharmacokinetic (PK) variability have been extensively studied, but few data on their intraindividual PK variability are available. In this article, we reviewed the published population compartmental models used to describe the time-varying PK of mAbs in clinical settings. Of 189 publications, 13 report the use of time-varying parameters and 30 describe the effects of antidrug antibody (ADA) development. Currently published time-varying models mainly describe fast decreases in clearance due to target-mediated elimination or slow decreases in clearance owing to cachexia reduction. Immunogenicity models mostly describe 'on-off' increases of clearance due to a rapid elimination of mAbs-ADA complexes. Some more sophisticated models attempted to decipher the time course of immunogenic response, notably by accounting for the time of onset and progressive increase in ADA production. Currently available time-varying and immunogenicity models are empirical approximations of the complex mAb disposition, but they emphasize the necessity to account for the temporal variations of mAb PK in model building. The clinical implications of the time-varying PK of mAbs are not fully understood, but some publications reported a link between clearance decrease and disease improvement. The future perspectives offered by this knowledge include the possibility to adapt the regimen to the disease and the patients' state, and also to immune status, and to monitor their evolution by monitoring PK variations.

Background: The treatment of multiple myeloma (MM) has been revolutionized by the introduction of therapeutic monoclonal antibodies (tmAbs). Daratumumab, a human IgG1/κ tmAb against CD38 on plasma cells, has improved overall survival in refractory MM and was recently approved as a frontline therapy for MM. Work on tmAb interference with serum protein electrophoresis (SPE) during MM monitoring has failed to provide information for laboratories on incidence of interference and effective methods of managing the interference at a practicable level. We aimed to evaluate daratumumab and elotuzumab interference in a large academic hospital setting and implement immediate solutions., Methods: We identified and chart reviewed all cases of possible daratumumab interference by electrophoretic pattern (120 of 1317 total cases over 3 months). We retrospectively reviewed SPE cases in our laboratory to assess clinical implications of tmAb interference before the laboratory was aware of tmAb treatment. We supplemented samples with daratumumab and elotuzumab to determine the limits of detection and run free light chain analysis., Results: Approximately 9% (120 of 1317) of tested cases have an SPE and/or immunofixation electrophoresis (IFE) pattern consistent with daratumumab, but only approximately 47% (56) of these cases were associated with daratumumab therapy. Presence of daratumumab led to physician misinterpretation of SPE/IFE results. Limits of daratumumab detection varied with total serum gammaglobulin concentrations, but serum free light chain analysis was unaffected., Conclusions: Clinical laboratories currently rely on interference identification by electrophoretic pattern, which may be insufficient and is inefficient. Critical tools in preventing misinterpretation efficiently include physician education, pharmacy notifications, separate order codes, and interpretive comments., (© 2019 American Association for Clinical Chemistry.)

Background and Objective: Echinacea angustifolia DC. and Zingiber officinale Roscoe are two natural products with documented immunomodulatory activity, both able to modulate the expression of important immune-related genes. Thus, their use in combination seems to be particularly promising. In this context, we have considered the oral supplementation of a highly standardized lipophilic extract combining both above-mentioned phytocomplexes, formulated in attractive softgel capsules, with two objectives: on the one hand to study oral pharmacokinetic of main active extracts' components and on the other hand to examine the immunomodulation and anti-inflammatory properties by gene expression profiling., Methods: Softgel capsules containing a combination of E. angustifolia DC. and Z. officinale Roscoe (5 mg and 25 mg, respectively) were given by oral administration to 10 healthy volunteers. The plasma concentrations of dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) for E. angustifolia DC., 6-gingerol and 6-shogaol (free and glucuronide) for Z. officinale Roscoe were determined by LC-MS analysis, and the pharmacokinetic analysis was performed. To understand the functional mechanisms responsible for the documented health benefits, we also examined the overall transcriptional remodeling induced in the peripheral blood mononuclear cells and performed an integrative functional analysis on the generated gene expression., Results: All bioactive components were absorbed very rapidly, and their t max were detected in plasma from 30 min to 1.40 h. The peak concentrations of tetraene, 6-gingerol, 6-shogaol and their glucuronide metabolites were 14.74, 5.66, 9.25, 29.2 and 22.24 ng/ml, respectively. Integrated analysis performed on the generated gene expression data highlighted immunomodulatory and anti-inflammatory effects similar to those exerted by hydrocortisone., Conclusion: These data demonstrated that the bioactive ingredients are highly and rapidly absorbed from softgel capsules containing the combination of the above-mentioned lipophilic extracts, providing evidence to support their immunomodulatory and anti-inflammatory properties. These data also help in defining the mechanistic pathways underlying the health benefits of these plant-derived bioactive compounds., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Objective: To determine the transfer of rituximab, an anti-CD20 monoclonal antibody widely used for neurologic conditions, into mature breast milk., Methods: Breast milk samples were collected from 9 women with MS who received rituximab 500 or 1,000 mg intravenous once or twice while breastfeeding from November 2017 to April 2019. Serial breast milk samples were collected before infusion and at 8 hours, 24 hours, 7 days, and 18-21 days after rituximab infusion in 4 patients. Five additional patients provided 1-2 samples at various times after rituximab infusion., Results: The median average rituximab concentration in mature breast milk was low at 0.063 μg/mL (range 0.046-0.097) in the 4 patients with serial breast milk collection, with an estimated median absolute infant dose of 0.0094 mg/kg/d and a relative infant dose (RID) of 0.08% (range 0.06%-0.10%). Most patients had a maximum concentration at 1-7 days after infusion. The maximum concentration occurred in a woman with a single breast milk sample and was 0.29 μg/mL at 11 days postinfusion, which corresponds with an estimated RID of 0.33%. Rituximab concentration in milk was virtually undetectable by 90 days postinfusion., Conclusions: We determined minimal transfer of rituximab into mature breast milk. The RID for rituximab was less than 0.4% and well below theoretically acceptable levels of less than 10%. Low oral bioavailability would probably also limit the absorption of rituximab by the newborn. In women with serious autoimmune neurologic conditions, monoclonal antibody therapy may afford an acceptable benefit to risk ratio, supporting both maternal treatment and breastfeeding., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)