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Pharmacokinetics/Pharmacodynamics of Nondepleting Anti-CD4 Monoclonal Antibody (TRX1) in Healthy Human Volunteers

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Purpose

TRX1 is a nondepleting anti-CD4 monoclonal IgG1 antibody being developed to induce tolerance by blocking CD4-mediated functions. The purpose of this study is to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of TRX1 and to develop a receptor-mediated PK/PD model that characterizes the relationships between serum TRX1 concentration and total and free CD4 expression in healthy male volunteers.

Methods

Nine subjects from three dosing cohorts in double-blinded, placebo-controlled phase I clinical study was included in the analysis. Serum TRX1 levels were determined using enzyme-linked immunosorbent assay. Blood total and free CD4 receptor levels were determined by using flow cytometric analyses. The receptor-mediated PK/PD model was developed to describe the dynamic interaction of TRX1 binding with CD4 receptors.

Results and Conclusions

TRX1 displayed nonlinear pharmacokinetic behavior and the CD4 receptors on T cells were saturated and down-modulated following treatment with TRX1. Results from in vitro studies using purified human T cells suggested that CD4-mediated internalization may constitute one pathway by which CD4 is down-modulated and TRX1 is cleared in vivo. The developed receptor-mediated PK/PD model adequately described the data. This PK/PD model was used to simulate PK/PD time profiles after different dosing regimens to help guide the dose selection in future clinical studies.

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Authors and Affiliations

  1. Department of Pharmacokinetic and Pharmacodynamic Sciences, MS 70, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA

    Chee M. Ng, Eric Stefanich, Banmeet S. Anand & Paul J. Fielder

  2. TolerRx Inc., Cambridge, MA, USA

    Louis Vaickus

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  1. Chee M. Ng
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  2. Eric Stefanich
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  3. Banmeet S. Anand
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  4. Paul J. Fielder
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  5. Louis Vaickus
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Correspondence to Chee M. Ng.

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Ng, C.M., Stefanich, E., Anand, B.S. et al. Pharmacokinetics/Pharmacodynamics of Nondepleting Anti-CD4 Monoclonal Antibody (TRX1) in Healthy Human Volunteers. Pharm Res 23, 95–103 (2006). https://doi.org/10.1007/s11095-005-8814-3

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  • DOI: https://doi.org/10.1007/s11095-005-8814-3

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