Abstract
Post-translational modifications (PTMs) of therapeutic monoclonal antibodies (mAbs) are important product quality attributes (PQAs) that can potentially impact drug stability, safety, and efficacy. The PTMs of a mAb may change remarkably in the bloodstream after drug administration compared to in vitro conditions. Thus, monitoring in vivo PTM changes of mAbs helps evaluate the criticality of PQAs during the product risk assessment. In addition, quantitation of the subject exposures to PTM variants helps assess the impact of PTMs on the safety and efficacy of therapeutic mAbs. Here, we developed an immunocapture-liquid chromatography/mass spectrometry (LC/MS) method to quantify in vivo PTM changes a therapeutic mAb overtime in single- and multiple-dose monkey pharmacokinetic (PK) studies. We also built mathematical models to predict the in vivo serum concentrations of PQAs, the subject exposures to PQAs, and the relative abundance of PQAs in single- and multiple-dose regimens. The model predictions are in good agreement with the experimental results. The immunocapture-LC/MS method and mathematical models enable bioanalytical chemists to quantitatively assess the criticality of PQAs during drug development.
Highlights
Therapeutic monoclonal antibodies produced in mammalian cells are heterogeneous as a result of post-translational modifications (PTMs)
If an animal was determined to be in overt pain/distress, or appears moribund and was beyond the point where recovery appears reasonable, the animal was euthanized for humane reasons in accordance with the American Veterinary Medical Association (AVMA) Guidelines on Euthanasia and with the procedures outlined in the protocol
The in vivo behaviors of MAB1 with site-specific PTMs were assessed in both single- and multiple-dose monkey PK studies
Summary
Therapeutic monoclonal antibodies (mAbs) produced in mammalian cells are heterogeneous as a result of post-translational modifications (PTMs). PTMs can occur during mAb production, purification, storage, and post-administration[1,2,3,4]. PTMs are a therapeutic mAb product quality attributes (PQAs). Controlling PQAs within predefined acceptance criteria is vital to the biopharmaceutical industry because it ensures consistent product quality and reduces potential impacts on drug safety and efficacy[5]. The modifications that occur during drug production and storage can be reliably monitored and controlled. Additional modifications may occur after drug administration as a result of the different environments encountered by mAbs in vivo versus in vitro.
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