The Experts below are selected from a list of 48 Experts worldwide ranked by ideXlab platform

Timothy K. Hart - One of the best experts on this subject based on the ideXlab platform.

  • Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero.
    Human & Experimental Toxicology, 2020
    Co-Authors: Danuta J. Herzyk, Timothy K. Hart, Peter J. Bugelski, Patrick J. Wier
    Abstract:

    Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a pre- and postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (FO) with Keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with Keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of pre- and postnatal development designed in accordance with ICH Guidelines.

  • Immunomodulatory Effects of Anti-CD4 Antibody in Host Resistance against Infections and Tumors in Human CD4 Transgenic Mice
    Infection and Immunity, 2001
    Co-Authors: Danuta J. Herzyk, Elizabeth R. Gore, Rodd Polsky, Kimberly L. Nadwodny, Curtis Maier, Timothy K. Hart, Allen G. Harmsen, Peter J. Bugelski
    Abstract:

    Anti-CD4 antibodies, which cause CD4+ T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody Keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4+ T cells by Keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with Keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of Keliximab. This was further demonstrated by the differential effect of Keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of Keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4+ T lymphocytes, Keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, Keliximab therapy may be beneficial in controlling certain autoimmune diseases.

  • comparative pharmacodynamics of Keliximab and clenoliximab in transgenic mice bearing human cd4
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Amarnath Sharma, Danuta J. Herzyk, Elizabeth R. Gore, Charles B. Davis, Lee Ann P Tobia, Deborah C Kwok, Marcella G Tucci, Timothy K. Hart
    Abstract:

    Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5–125 mg/kg). The PK of Keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4 + T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity ( R max ) of PD effects was increased, and the time to reach R max shifted to later times. At all three dose levels, Keliximab caused a relatively rapid decline in the number of circulating CD4 + T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4 + T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4 + T cells. Keliximab appeared to be more potent and efficient in depleting CD4 + T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

  • Flow Cytometry in the Preclinical Development of Biopharmaceuticals
    Toxicologic Pathology, 1999
    Co-Authors: Kent A. Gossett, Danuta J. Herzyk, Elizabeth R. Gore, Timothy K. Hart, Padma K. Narayanan, Donna M. Williams, Teresa S. Sellers
    Abstract:

    Novel biomarkers are often required in the preclinical development of biopharmaceuticals in order to characterize pharmacologic and toxicologic effects and to establish pharmacodynamic and pharmacokinetic relationships. Flow cytometry is uniquely suited for measurement of these biomarkers. Large numbers of single cells in a heterogeneous population can be rapidly identified and characterized with high accuracy and reproducibility. Cells are not damaged by the detection system and can be subsequently sorted for further morphologic or functional analysis. The availability of clinical instruments and a wide range of fluorescent probes have made this technology applicable for use in toxicologic clinical pathology. Flow cytometry has played an integral role in the development of a monoclonal antibody to human CD4 (Keliximab, IDEC-CE9.1, SB 210396). Lymphocyte subset analysis and assays for expression, coating, and modulation of human CD4 were used for sequential assessment of the pharmacologic activity of keli...

Mark Larche - One of the best experts on this subject based on the ideXlab platform.

  • the effects of an anti cd4 monoclonal antibody Keliximab on peripheral blood cd4 t cells in asthma
    European Respiratory Journal, 2001
    Co-Authors: B S Sihra, Chris Compton, Neil Barnes, J Barkans, Mark Larche
    Abstract:

    CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of Keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics. Three cohorts of patients (termed C 0.5 : n=6, C 1.5 : n=5, and C 3.0 : n=5) received a single infusion of 0.5, 1.5 or 3.0 mg·kg −1 , respectively, with a fourth receiving placebo (C pl : n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-γ, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab9s in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated. There was a significant increase in lung function (peak expiratory flow rate) in the C 3.0 group. Following infusion in C 0.5 , C 1.5 and C 3.0 but not C pl : 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-γ, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody. Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of Keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.

B S Sihra - One of the best experts on this subject based on the ideXlab platform.

  • the effects of an anti cd4 monoclonal antibody Keliximab on peripheral blood cd4 t cells in asthma
    European Respiratory Journal, 2001
    Co-Authors: B S Sihra, Chris Compton, Neil Barnes, J Barkans, Mark Larche
    Abstract:

    CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of Keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics. Three cohorts of patients (termed C 0.5 : n=6, C 1.5 : n=5, and C 3.0 : n=5) received a single infusion of 0.5, 1.5 or 3.0 mg·kg −1 , respectively, with a fourth receiving placebo (C pl : n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-γ, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab9s in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated. There was a significant increase in lung function (peak expiratory flow rate) in the C 3.0 group. Following infusion in C 0.5 , C 1.5 and C 3.0 but not C pl : 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-γ, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody. Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of Keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.

  • randomised dose ranging placebo controlled study of chimeric antibody to cd4 Keliximab in chronic severe asthma
    The Lancet, 1998
    Co-Authors: B S Sihra, Chris Compton, Thomas Leonard, Neil Barnes
    Abstract:

    BACKGROUND: There is substantial circumstantial evidence that CD4 lymphocytes have a role in the pathogenesis of chronic asthma. We investigated the efficacy and safety in severe corticosteroid-dependent asthma of a single intravenous infusion of Keliximab (IDEC CE9.1), a chimeric monoclonal antibody to CD4. METHODS: 22 patients were recruited from two asthma clinics. In an ascending-dose design, the first eight patients were assigned 0.5 mg/kg Keliximab (six) or placebo (two); the next seven were assigned 1.5 mg/kg (five) or placebo (two); and the last seven were assigned 3.0 mg/kg (five) or placebo (two). Masked data on safety for each dose group were assessed before progression to the next dose. Patients kept a daily symptom diary and measured morning and evening peak expiratory flow (PEF) at home. PEF and forced expiratory volume in 1 s (FEV1) were measured at follow-up clinic visits. FINDINGS: Patients given 0.5 mg/kg or 1.5 mg/kg Keliximab and placebo recipients did not differ in change from baseline of PEF, FEV1, or symptom score. Those given 3.0 mg/kg Keliximab differed significantly from placebo recipients in change in morning PEF (median area under curve [AUC] 445 vs -82.5, p=0.005) and evening PEF (median AUC 548 vs -85, p=0.014). Symptom score showed the same pattern (though differences did not achieve significance), but there was no difference in clinic FEV1. There were no serious adverse effects related to treatment. Two patients had mild exacerbations of eczema and one developed a transient maculopapular rash. All doses of Keliximab were associated with a reduction from baseline in CD4 count. INTERPRETATION: Our findings raise the possibility that T-cell-directed treatment may be an alternative approach to the treatment of severe asthma.

Danuta J. Herzyk - One of the best experts on this subject based on the ideXlab platform.

  • Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero.
    Human & Experimental Toxicology, 2020
    Co-Authors: Danuta J. Herzyk, Timothy K. Hart, Peter J. Bugelski, Patrick J. Wier
    Abstract:

    Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a pre- and postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (FO) with Keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with Keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of pre- and postnatal development designed in accordance with ICH Guidelines.

  • Immunomodulatory Effects of Anti-CD4 Antibody in Host Resistance against Infections and Tumors in Human CD4 Transgenic Mice
    Infection and Immunity, 2001
    Co-Authors: Danuta J. Herzyk, Elizabeth R. Gore, Rodd Polsky, Kimberly L. Nadwodny, Curtis Maier, Timothy K. Hart, Allen G. Harmsen, Peter J. Bugelski
    Abstract:

    Anti-CD4 antibodies, which cause CD4+ T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody Keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4+ T cells by Keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with Keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of Keliximab. This was further demonstrated by the differential effect of Keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of Keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4+ T lymphocytes, Keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, Keliximab therapy may be beneficial in controlling certain autoimmune diseases.

  • comparative pharmacodynamics of Keliximab and clenoliximab in transgenic mice bearing human cd4
    Journal of Pharmacology and Experimental Therapeutics, 2000
    Co-Authors: Amarnath Sharma, Danuta J. Herzyk, Elizabeth R. Gore, Charles B. Davis, Lee Ann P Tobia, Deborah C Kwok, Marcella G Tucci, Timothy K. Hart
    Abstract:

    Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5–125 mg/kg). The PK of Keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4 + T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity ( R max ) of PD effects was increased, and the time to reach R max shifted to later times. At all three dose levels, Keliximab caused a relatively rapid decline in the number of circulating CD4 + T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4 + T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4 + T cells. Keliximab appeared to be more potent and efficient in depleting CD4 + T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

  • Flow Cytometry in the Preclinical Development of Biopharmaceuticals
    Toxicologic Pathology, 1999
    Co-Authors: Kent A. Gossett, Danuta J. Herzyk, Elizabeth R. Gore, Timothy K. Hart, Padma K. Narayanan, Donna M. Williams, Teresa S. Sellers
    Abstract:

    Novel biomarkers are often required in the preclinical development of biopharmaceuticals in order to characterize pharmacologic and toxicologic effects and to establish pharmacodynamic and pharmacokinetic relationships. Flow cytometry is uniquely suited for measurement of these biomarkers. Large numbers of single cells in a heterogeneous population can be rapidly identified and characterized with high accuracy and reproducibility. Cells are not damaged by the detection system and can be subsequently sorted for further morphologic or functional analysis. The availability of clinical instruments and a wide range of fluorescent probes have made this technology applicable for use in toxicologic clinical pathology. Flow cytometry has played an integral role in the development of a monoclonal antibody to human CD4 (Keliximab, IDEC-CE9.1, SB 210396). Lymphocyte subset analysis and assays for expression, coating, and modulation of human CD4 were used for sequential assessment of the pharmacologic activity of keli...

Neil Barnes - One of the best experts on this subject based on the ideXlab platform.

  • the effects of an anti cd4 monoclonal antibody Keliximab on peripheral blood cd4 t cells in asthma
    European Respiratory Journal, 2001
    Co-Authors: B S Sihra, Chris Compton, Neil Barnes, J Barkans, Mark Larche
    Abstract:

    CD4+ T-cells are likely to be involved as a source of pro-inflammatory cytokines in asthma. This study assessed the effects of an infusion of Keliximab (IDEC CE9.1), an anti-CD4+ monoclonal antibody, on peripheral blood CD4+ T-cells in corticosteroid-dependent asthmatics. Three cohorts of patients (termed C 0.5 : n=6, C 1.5 : n=5, and C 3.0 : n=5) received a single infusion of 0.5, 1.5 or 3.0 mg·kg −1 , respectively, with a fourth receiving placebo (C pl : n=6), and were followed-up for 4 weeks. By flow cytometry in peripheral blood, pre- and postinfusion assessment was made of: a) CD4 and CD8 counts and mean fluorescence; b) CD25, human leukocyte antigen-DR (HLA-DR), CD45RO and CD45RA expression on CD4+ T-cells; and c) interferon (IFN)-γ, interleukin (IL)-4 and IL-5 expression in CD4+ T-cells. Keliximab9s in vitro effects on allergen-specific peripheral blood mononuclear cells (PBMC) proliferation in atopic asthmatics were also evaluated. There was a significant increase in lung function (peak expiratory flow rate) in the C 3.0 group. Following infusion in C 0.5 , C 1.5 and C 3.0 but not C pl : 1) the CD4, but not CD8 count was significantly decreased; 2) there was total loss of Leu3a staining; 3) there were significant reductions in the mean fluorescence of OKT4 binding; and 4) there were significant reductions in the numbers of CD25, HLA-DR, CD45RO and CD45RA/CD4+ cells. There were no changes in CD4+ cell expression of IFN-γ, IL-4 or IL-5. Keliximab caused a significant reduction in T-cell proliferation as compared to a control monoclonal antibody. Keliximab, as an anti-CD4 monoclonal antibody, leads to a transient reduction in the number of CD4+ T-cells and modulation of CD4+ receptor expression in severe asthmatics. The effects of Keliximab may be mediated through a decrease in CD4+ surface expression and T-lymphocyte numbers, in addition to a reduction in allergen-induced proliferation.

  • randomised dose ranging placebo controlled study of chimeric antibody to cd4 Keliximab in chronic severe asthma
    The Lancet, 1998
    Co-Authors: B S Sihra, Chris Compton, Thomas Leonard, Neil Barnes
    Abstract:

    BACKGROUND: There is substantial circumstantial evidence that CD4 lymphocytes have a role in the pathogenesis of chronic asthma. We investigated the efficacy and safety in severe corticosteroid-dependent asthma of a single intravenous infusion of Keliximab (IDEC CE9.1), a chimeric monoclonal antibody to CD4. METHODS: 22 patients were recruited from two asthma clinics. In an ascending-dose design, the first eight patients were assigned 0.5 mg/kg Keliximab (six) or placebo (two); the next seven were assigned 1.5 mg/kg (five) or placebo (two); and the last seven were assigned 3.0 mg/kg (five) or placebo (two). Masked data on safety for each dose group were assessed before progression to the next dose. Patients kept a daily symptom diary and measured morning and evening peak expiratory flow (PEF) at home. PEF and forced expiratory volume in 1 s (FEV1) were measured at follow-up clinic visits. FINDINGS: Patients given 0.5 mg/kg or 1.5 mg/kg Keliximab and placebo recipients did not differ in change from baseline of PEF, FEV1, or symptom score. Those given 3.0 mg/kg Keliximab differed significantly from placebo recipients in change in morning PEF (median area under curve [AUC] 445 vs -82.5, p=0.005) and evening PEF (median AUC 548 vs -85, p=0.014). Symptom score showed the same pattern (though differences did not achieve significance), but there was no difference in clinic FEV1. There were no serious adverse effects related to treatment. Two patients had mild exacerbations of eczema and one developed a transient maculopapular rash. All doses of Keliximab were associated with a reduction from baseline in CD4 count. INTERPRETATION: Our findings raise the possibility that T-cell-directed treatment may be an alternative approach to the treatment of severe asthma.