Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development

Abstract

Abstract. Antibodies or antibody-related fusion proteins binding to soluble antigens in plasma form an important subclass of approved therapeutics. Pharmaceutical companies are constantly trying to accelerate the pace of drug discovery and development of these antibodies and identify superior candidates in face of significant attrition rates. Understanding the interplay between drug-and targetrelated factors on magnitude and duration of target inhibition is imperative for successful advancement of these therapeutics. Simulations using a target-mediated drug disposition model were performed to evaluate the influence of antibody-target binding affinity, baseline target concentration, and target turnover on magnitude and duration of soluble target inhibition. These simulations assumed intravenous dosing of the antibody and evaluated multiple parameters over a wide range. These simulations reveal that improvement in affinity reaches a point of diminishing returns following which further improvement in affinity does not alter the magnitude and more importantly the duration of target inhibition. Evaluation of unbound antibody and target kinetics indicated that point of diminishing returns in duration of inhibition was due to target-mediated binding and subsequent elimination of antibody at later time points. Similarly, influence of baseline target concentration and target turnover on magnitude and duration of target inhibition in plasma is shown. Additionally, the fraction of dose eliminated via target mediated elimination (Fel ™ ) can be a useful tool to enable selection of strategies to increase duration of target inhibition. The implications of these simulations in drug discovery and development with regard to target identification, antibody optimization, and backup candidate selection are discussed.

A Tutorial on Target-Mediated Drug Disposition (TMDD) Models

“…Chimalakonda et al 13 investigated the percentage inhibition of the receptor and confirmed that decreasing K D by increasing k on resulted in lowering the minimum concentration of the receptor and improving the duration of receptor inhibition. However, the maximum duration of receptor inhibition was found to be fixed for a particular antibody and dose, regardless of its binding rate.…”

“…Chimalakonda et al . investigated the percentage inhibition of the receptor and confirmed that decreasing K D by increasing resulted in lowering the minimum concentration of the receptor and improving the duration of receptor inhibition.…”

AFIR: A Dimensionless Potency Metric for Characterizing the Activity of Monoclonal Antibodies

“…17 Modelers have sought to develop rules of thumb for predicting how changing the drug properties or dosing regimen will impact measures of drug activity, such as maximum target inhibition or duration of effect of a single dose. [18][19][20][21][22] Thus far, the existing metrics and analyses apply only to single-dose scenarios, which is of limited value because most mAbs are dosed repeatedly in the clinic.…”

Development of New Strategies for Malaria Chemoprophylaxis: From Monoclonal Antibodies to Long-Acting Injectable Drugs

“…This translates to a twofold difference in dosing (as measured by mg/kg) to achieve similar efficacies in mice and humans. This in turn suggests a required antigenic potency (EC 50 ) below 100 pM (<15 ng/mL [65,66]. It will also be important to show that there is no antibody-dependent enhancement [67].…”