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  1. Article: Estimating the contribution of genes and environment to variation in renal drug clearance.

    Leabman, Maya K / Giacomini, Kathleen M

    Pharmacogenetics

    2003  Volume 13, Issue 9, Page(s) 581–584

    Abstract: Renal excretion is the major pathway for elimination of many clinically used drugs and xenobiotics. We estimated the genetic component (rGC) contributing to variation in renal clearance for six compounds (amoxicillin, ampicillin, metformin, terodiline, ... ...

    Abstract Renal excretion is the major pathway for elimination of many clinically used drugs and xenobiotics. We estimated the genetic component (rGC) contributing to variation in renal clearance for six compounds (amoxicillin, ampicillin, metformin, terodiline, digoxin and iohexol) using Repeated Drug Application methodology. Data were obtained from published literature. The rGC values of renal clearance of metformin, amoxicillin, and ampicillin, which undergo transporter-mediated secretion, ranged from 0.64-0.94. This finding suggests that variation in the renal clearance of these drugs has a strong genetic component. Additionally, the rGC values of renal clearance of metformin, amoxicillin, and ampicillin were similar to previously reported rGC values for metabolism. By contrast, the rGC values of renal clearance for iohexol, digoxin, and terodiline were low (0.12-0.37). Renal clearance of these compounds occurs mainly through passive processes (e.g. glomerular filtration and passive secretion/reabsorption). The low rGC values of iohexol, digoxin and terodiline suggest that environmental factors may contribute to variation in their renal clearance.
    MeSH term(s) Amoxicillin/pharmacokinetics ; Ampicillin/pharmacokinetics ; Anti-Bacterial Agents/pharmacokinetics ; Butylamines/pharmacokinetics ; Calcium Channel Blockers/pharmacokinetics ; Cardiotonic Agents/pharmacokinetics ; Contrast Media/pharmacokinetics ; Digoxin/pharmacokinetics ; Environment ; Genes ; Genetic Variation ; Glomerular Filtration Rate ; Humans ; Hypoglycemic Agents/pharmacokinetics ; Iohexol/pharmacokinetics ; Kidney/metabolism ; Metabolic Clearance Rate ; Metformin/pharmacokinetics
    Chemical Substances Anti-Bacterial Agents ; Butylamines ; Calcium Channel Blockers ; Cardiotonic Agents ; Contrast Media ; Hypoglycemic Agents ; Iohexol (4419T9MX03) ; terodiline (70KG06964W) ; Digoxin (73K4184T59) ; Ampicillin (7C782967RD) ; Amoxicillin (804826J2HU) ; Metformin (9100L32L2N)
    Language English
    Publishing date 2003-11-19
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1146969-9
    ISSN 0960-314X
    ISSN 0960-314X
    DOI 10.1097/00008571-200309000-00007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3660: Show issues Location:
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  2. Article ; Online: Effects of altered FcγR binding on antibody pharmacokinetics in cynomolgus monkeys.

    Leabman, Maya K / Meng, Y Gloria / Kelley, Robert F / DeForge, Laura E / Cowan, Kyra J / Iyer, Suhasini

    mAbs

    2014  Volume 5, Issue 6, Page(s) 896–903

    Abstract: Antibody interactions with Fcγ receptors (FcγRs), like FcγRIIIA, play a critical role in mediating antibody effector functions and thereby contribute significantly to the biologic and therapeutic activity of antibodies. Over the past decade, considerable ...

    Abstract Antibody interactions with Fcγ receptors (FcγRs), like FcγRIIIA, play a critical role in mediating antibody effector functions and thereby contribute significantly to the biologic and therapeutic activity of antibodies. Over the past decade, considerable work has been directed towards production of antibodies with altered binding affinity to FcγRs and evaluation of how the alterations modulate their therapeutic activity. This has been achieved by altering glycosylation status at N297 or by engineering modifications in the crystallizable fragment (Fc) region. While the effects of these modifications on biologic activity and efficacy have been examined, few studies have been conducted to understand their effect on antibody pharmacokinetics (PK). We present here a retrospective analysis in which we characterize the PK of three antibody variants with decreased FcγR binding affinity caused by amino acid substitutions in the Fc region (N297A, N297G, and L234A/L235A) and three antibody variants with increased FcγRIIIA binding affinity caused by afucosylation at N297, and compare their PK to corresponding wild type antibody PK in cynomolgus monkeys. For all antibodies, PK was examined at a dose that was known to be in the linear range. Since production of the N297A and N297G variants in Chinese hamster ovary cells results in aglycosylated antibodies that do not bind to FcγRs, we also examined the effect of expression of an aglycosylated antibody, without sequence change(s), in E. coli. All the variants demonstrated similar PK compared with that of the wild type antibodies, suggesting that, for the six antibodies presented here, altered FcγR binding affinity does not affect PK.
    MeSH term(s) Animals ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/pharmacokinetics ; Cricetinae ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Genetic Variation ; Macaca fascicularis ; Protein Binding ; Receptors, Fc/metabolism
    Chemical Substances Antibodies, Monoclonal ; Receptors, Fc
    Language English
    Publishing date 2014-01-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2537838-7
    ISSN 1942-0870 ; 1942-0870
    ISSN (online) 1942-0870
    ISSN 1942-0870
    DOI 10.4161/mabs.26436
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Critical role of bioanalytical strategies in investigation of clinical PK observations, a Phase I case study.

    Peng, Kun / Xu, Keyang / Liu, Luna / Hendricks, Robert / Delarosa, Reginald / Erickson, Rich / Budha, Nageshwar / Leabman, Maya / Song, An / Kaur, Surinder / Fischer, Saloumeh K

    mAbs

    2014  Volume 6, Issue 6, Page(s) 1500–1508

    Abstract: RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was ... ...

    Abstract RG7652 is a human immunoglobulin 1 (IgG1) monoclonal antibody (mAb) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) and is designed for the treatment of hypercholesterolemia. A target-binding enzyme-linked immunosorbent assay (ELISA) was developed to measure RG7652 levels in human serum in a Phase I study. Although target-binding assay formats are generally used to quantify free therapeutic, the actual therapeutic species being measured are affected by assay conditions, such as sample dilution and incubation time, and levels of soluble target in the samples. Therefore, in the presence of high concentrations of circulating target, the choice of reagents and assay conditions can have a significant effect on the observed pharmacokinetic (PK) profiles. Phase I RG7652 PK analysis using the ELISA data resulted in a nonlinear dose normalized exposure. An investigation was conducted to characterize the ELISA to determine whether the assay format and reagents may have contributed to the PK observation. In addition, to confirm the ELISA results, a second orthogonal method, liquid chromatography tandem mass spectrometry (LC-MS/MS) using a signature peptide as surrogate, was developed and implemented. A subset of PK samples, randomly selected from half of the subjects in the 6 single ascending dose (SAD) cohorts in the Phase I clinical study, was analyzed with the LC-MS/MS assay, and the data were found to be comparable to the ELISA data. This paper illustrates the importance of reagent characterization, as well as the benefits of using an orthogonal approach to eliminate bioanalytical contributions when encountering unexpected observations.
    MeSH term(s) Antibodies, Monoclonal/blood ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacokinetics ; Chromatography, Liquid ; Cohort Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunoglobulin G/blood ; Immunoglobulin G/immunology ; Proprotein Convertase 9 ; Proprotein Convertases/immunology ; Serine Endopeptidases/immunology ; Tandem Mass Spectrometry
    Chemical Substances Antibodies, Monoclonal ; Immunoglobulin G ; RG7652 ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2014
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ISSN 1942-0870
    ISSN (online) 1942-0870
    DOI 10.4161/mabs.36208
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  4. Article ; Online: Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.

    Budha, Nageshwar R / Leabman, Maya / Jin, Jin Y / Wada, D Russell / Baruch, Amos / Peng, Kun / Tingley, Whittemore G / Davis, John D

    The AAPS journal

    2015  Volume 17, Issue 4, Page(s) 881–890

    Abstract: RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in ... ...

    Abstract RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple subcutaneous doses. Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to explain the antibody PK and LDLc time course data. The PK and PD models based on data from healthy subjects were used to simulate the effects of RG7652 on LDLc levels for a range of potential dose regimens in patients with coronary heart disease. A one-compartment PK model combined with an indirect PD response model was able to adequately describe the PK and LDLc data. Simulations of 400 mg every 4 weeks or 800 mg every 8 weeks regimens show significant LDLc reduction and suggest that dosing RG7652 once every month or once every 2 months is predicted to be optimal for the treatment of hypercholesterolemia. The PK and PD model successfully described the PK and LDLc data from healthy subjects in a Phase 1 study, and the model-based simulations provided useful insights and quantitative understanding for the selection of Phase 2 study doses in patients with coronary heart disease. The approach used in the case study demonstrates the utility of modeling and simulation in designing dose-ranging studies.
    MeSH term(s) Adult ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Cholesterol, LDL/blood ; Computer Simulation ; Dose-Response Relationship, Drug ; Female ; Humans ; Hypercholesterolemia/drug therapy ; Male ; Middle Aged ; Models, Biological ; Proprotein Convertase 9 ; Proprotein Convertases/antagonists & inhibitors ; Serine Endopeptidases ; Young Adult
    Chemical Substances Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Cholesterol, LDL ; RG7652 ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2015-03-31
    Publishing country United States
    Document type Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial
    ISSN 1550-7416
    ISSN (online) 1550-7416
    DOI 10.1208/s12248-015-9750-8
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  5. Article: Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants.

    Fujita, Tomoe / Urban, Thomas J / Leabman, Maya K / Fujita, Kazumi / Giacomini, Kathleen M

    Journal of pharmaceutical sciences

    2006  Volume 95, Issue 1, Page(s) 25–36

    Abstract: The human organic cation transporter 2 (OCT2, SLC22A2) is a multispecific transporter of organic cations, including many clinically used drugs. OCT2 is primarily responsible for the uptake of organic cations across the basolateral membrane of renal ... ...

    Abstract The human organic cation transporter 2 (OCT2, SLC22A2) is a multispecific transporter of organic cations, including many clinically used drugs. OCT2 is primarily responsible for the uptake of organic cations across the basolateral membrane of renal tubular epithelial cells and is considered a major transporter in the active secretion of organic cations in the kidney. Uptake of organic cations by OCT2 is driven by the inside-negative membrane potential and is pH-sensitive. Regulation of OCT2 at the transcriptional level by steroid hormones and at the protein level by various protein kinases has been described. Several human genetic variants in the coding region of OCT2 have been identified and functionally characterized, including both polymorphic and rare variants. A variety of structurally diverse compounds have been shown to interact with OCT2, including endogenous compounds, drugs, and dietary supplements.
    MeSH term(s) Animals ; Dietary Supplements ; Genetic Variation ; Humans ; Kidney/metabolism ; Organic Cation Transport Proteins/genetics ; Organic Cation Transport Proteins/metabolism ; Organic Cation Transporter 2 ; Pharmaceutical Preparations/metabolism
    Chemical Substances Organic Cation Transport Proteins ; Organic Cation Transporter 2 ; Pharmaceutical Preparations ; SLC22A2 protein, human
    Language English
    Publishing date 2006-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 3151-3
    ISSN 1520-6017 ; 0022-3549
    ISSN (online) 1520-6017
    ISSN 0022-3549
    DOI 10.1002/jps.20536
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  6. Article ; Online: Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates.

    Yeung, Yik Andy / Leabman, Maya K / Marvin, Jonathan S / Qiu, Julia / Adams, Camellia W / Lien, Samantha / Starovasnik, Melissa A / Lowman, Henry B

    Journal of immunology (Baltimore, Md. : 1950)

    2009  Volume 182, Issue 12, Page(s) 7663–7671

    Abstract: The pH-dependent binding of Igs to the neonatal FcR (FcRn) plays a critical role in the in vivo homeostasis of IgGs. Modulating the interaction between Fc and FcRn through protein engineering is one method for improving the pharmacokinetics of ... ...

    Abstract The pH-dependent binding of Igs to the neonatal FcR (FcRn) plays a critical role in the in vivo homeostasis of IgGs. Modulating the interaction between Fc and FcRn through protein engineering is one method for improving the pharmacokinetics of therapeutic Abs. Recent studies disputed the direct relationship between increasing FcRn affinity and improved pharmacokinetic properties. In this work, we studied the pharmacokinetics of two human IgG1 Fc variants in cynomolgus monkey to further clarify the affinity-pharmacokinetic relationship. First, we report a number of novel Fc point mutations and combination variants, including some with primate-specific FcRn-binding improvements. By studying these variants along with some previously described variants across a wide range of affinities, we discovered a direct correlation of pH 6 affinity improvements with neutral pH improvements, suggesting that all of the tested variants exhibit similar pH dependency in FcRn binding. We then evaluated the pharmacokinetics of variants N434A and N434W, which, respectively, gave approximately 4- and 80-fold improvements in pH 6-binding affinity to both human and nonhuman primate FcRn. Surprisingly, clearance of N434W was similar to that of wild type. N434W is the first variant studied in primates that exhibits significant binding to FcRn at pH 7.4, and its clearance substantiates the principle that too much affinity improvement, i.e., beyond that of N434W, does not yield improved pharmacokinetics. In contrast, N434A exhibited a approximately 2-fold decrease in clearance in cynomolgus monkey, supporting the notion that modest increases in pH 6 FcRn affinity can result in improved pharmacokinetics in primates.
    MeSH term(s) Amino Acid Sequence ; Animals ; Antibody Affinity/immunology ; Histocompatibility Antigens Class I/immunology ; Humans ; Hydrogen-Ion Concentration ; Immunoglobulin G/genetics ; Immunoglobulin G/immunology ; Immunoglobulin G/metabolism ; Immunoglobulin G/pharmacology ; Macaca fascicularis/immunology ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Structure, Quaternary ; Receptors, Fc/immunology ; Recombinant Proteins/genetics ; Recombinant Proteins/immunology ; Recombinant Proteins/metabolism ; Recombinant Proteins/pharmacology
    Chemical Substances Fc receptor, neonatal ; Histocompatibility Antigens Class I ; Immunoglobulin G ; Receptors, Fc ; Recombinant Proteins
    Language English
    Publishing date 2009-06-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.0804182
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  7. Article: Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2).

    Dresser, Mark J / Xiao, Guangqing / Leabman, Maya K / Gray, Andrew T / Giacomini, Kathleen M

    Pharmaceutical research

    2002  Volume 19, Issue 8, Page(s) 1244–1247

    MeSH term(s) Animals ; Biguanides/chemistry ; Biguanides/pharmacokinetics ; Female ; Humans ; Organic Cation Transport Proteins/metabolism ; Organic Cation Transporter 2 ; Quaternary Ammonium Compounds/chemistry ; Quaternary Ammonium Compounds/pharmacokinetics ; Xenopus laevis
    Chemical Substances Biguanides ; Organic Cation Transport Proteins ; Organic Cation Transporter 2 ; Quaternary Ammonium Compounds ; SLC22A2 protein, human
    Language English
    Publishing date 2002-08
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 843063-9
    ISSN 1573-904X ; 0724-8741 ; 0739-0742
    ISSN (online) 1573-904X
    ISSN 0724-8741 ; 0739-0742
    DOI 10.1023/a:1019870831174
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  8. Article: Functional genomics of membrane transporters in human populations.

    Urban, Thomas J / Sebro, Ronnie / Hurowitz, Evan H / Leabman, Maya K / Badagnani, Ilaria / Lagpacan, Leah L / Risch, Neil / Giacomini, Kathleen M

    Genome research

    2006  Volume 16, Issue 2, Page(s) 223–230

    Abstract: Although considerable progress has been made toward characterizing human DNA sequence variation, there remains a deficiency in information on human phenotypic variation at the single-gene level. We systematically analyzed the function of all protein- ... ...

    Abstract Although considerable progress has been made toward characterizing human DNA sequence variation, there remains a deficiency in information on human phenotypic variation at the single-gene level. We systematically analyzed the function of all protein-altering variants of eleven membrane transporters in heterologous expression systems. Coding-region variants were identified by screening DNA from a large sample (n = 247-276) of ethnically diverse subjects. In total, we functionally analyzed 88 protein-altering variants. Fourteen percent of the polymorphic variants (defined as variants with allele frequencies > or =1% in at least one major ethnic group) had no activity or significantly reduced function. Decreased function variants had significantly lower allele frequencies and were more likely to alter evolutionarily conserved amino acid residues. However, variants at evolutionarily conserved positions with approximately normal activity in cellular assays were also at significantly lower allele frequencies, suggesting that some variants with apparently normal activity in biochemical assays may influence occult functions or quantitative degrees of function that are important in human fitness but not measured in these assays. For example, eight (14%) of the 58 variants for which we had measured the transport of at least two substrates showed substrate-specific defects in transport. These variants and the reduced function variants provide plausible candidates for disease susceptibility or variation in clinical drug response.
    MeSH term(s) Biological Transport/genetics ; Ethnic Groups ; Gene Expression/genetics ; Gene Frequency/genetics ; Genomics/methods ; Humans ; Membrane Transport Proteins/genetics ; Polymorphism, Genetic/genetics
    Chemical Substances Membrane Transport Proteins
    Language English
    Publishing date 2006-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.4356206
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  9. Article ; Online: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

    Herbst, Roy S / Soria, Jean-Charles / Kowanetz, Marcin / Fine, Gregg D / Hamid, Omid / Gordon, Michael S / Sosman, Jeffery A / McDermott, David F / Powderly, John D / Gettinger, Scott N / Kohrt, Holbrook E K / Horn, Leora / Lawrence, Donald P / Rost, Sandra / Leabman, Maya / Xiao, Yuanyuan / Mokatrin, Ahmad / Koeppen, Hartmut / Hegde, Priti S /
    Mellman, Ira / Chen, Daniel S / Hodi, F Stephen

    Nature

    2014  Volume 515, Issue 7528, Page(s) 563–567

    Abstract: The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing ... ...

    Abstract The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; B7-H1 Antigen/metabolism ; Biomarkers/blood ; CTLA-4 Antigen/metabolism ; Chemokine CX3CL1/metabolism ; Clinical Protocols ; Disease-Free Survival ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunotherapy/adverse effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Middle Aged ; Neoplasms/diagnosis ; Neoplasms/therapy ; Treatment Outcome ; Young Adult
    Chemical Substances Antibodies, Monoclonal ; B7-H1 Antigen ; Biomarkers ; CD274 protein, human ; CTLA-4 Antigen ; CTLA4 protein, human ; CX3CL1 protein, human ; Chemokine CX3CL1 ; atezolizumab (52CMI0WC3Y)
    Language English
    Publishing date 2014-11-27
    Publishing country England
    Document type Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature14011
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  10. Article ; Online: Combined administration of RG7652, a recombinant human monoclonal antibody against PCSK9, and atorvastatin does not result in reduction of immune function.

    Gelzleichter, Thomas R / Halpern, Wendy / Erwin, Roy / Baruch, Amos / Leabman, Maya / Forrest, Abigail S / Satterwhite, Christina M / Peng, Kun / Chilton, Jennifer / Stevens, Dale

    Toxicological sciences : an official journal of the Society of Toxicology

    2014  Volume 140, Issue 2, Page(s) 470–480

    Abstract: RG7652 is a human IgG1 monoclonal antibody designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to hepatic low density lipoprotein receptor (LDL-r), thereby blocking PCSK9-mediated degradation of LDL-r. This therapeutic ... ...

    Abstract RG7652 is a human IgG1 monoclonal antibody designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) binding to hepatic low density lipoprotein receptor (LDL-r), thereby blocking PCSK9-mediated degradation of LDL-r. This therapeutic candidate is under development for the prevention of cardiovascular mortality and morbidity in dyslipidemic patients. The primary objective of this study was to evaluate the potential immunotoxicological effects of RG7652 when given to cynomolgus monkeys either alone or in combination with a daily oral dose of atorvastatin. Administration of RG7652 via subcutaneous injection every other week for 12 weeks (a total of seven doses), daily oral doses of atorvastatin (total of 85 doses), and combinations of each up to 15 and 20 mg/kg/dose, respectively, were well tolerated and there was no evidence of alteration in immune function. Administration of pharmacologically relevant doses of RG7652 in combination with atorvastatin to healthy monkeys does not result in clinically meaningful immunosuppression as measured by T-cell dependent antibody responses, natural killer cell activity, immunophenotype, or delayed type hypersensitivity. The only pharmacologically mediated changes observed during the dosing period were the anticipated changes in circulating cholesterol.
    MeSH term(s) Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacology ; Anticholesteremic Agents/administration & dosage ; Atorvastatin Calcium ; Female ; Heptanoic Acids/administration & dosage ; Hypersensitivity, Delayed ; Macaca fascicularis ; Male ; Proprotein Convertase 9 ; Proprotein Convertases/immunology ; Pyrroles/administration & dosage ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/immunology ; Recombinant Proteins/pharmacology ; Serine Endopeptidases/immunology
    Chemical Substances Antibodies, Monoclonal ; Anticholesteremic Agents ; Heptanoic Acids ; Pyrroles ; RG7652 ; Recombinant Proteins ; Atorvastatin Calcium (48A5M73Z4Q) ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Proprotein Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
    Language English
    Publishing date 2014-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1420885-4
    ISSN 1096-0929 ; 1096-6080
    ISSN (online) 1096-0929
    ISSN 1096-6080
    DOI 10.1093/toxsci/kfu093
    Database MEDical Literature Analysis and Retrieval System OnLINE

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