Specificity and selectivity evaluations of ligand binding assay of protein therapeutics against concomitant drugs and related endogenous proteins.

Macromolecule drugs designed against specific target proteins/ receptors have been applied in combination therapies, especially for complex and related diseases such as cancer for synergistic efficacy and alleviation of side effects. Protein therapeutics are typically measured using ligand binding assays (LBA). Evaluating the specificity and selectivity of LBA against their target proteins or in instances where concomitantly administered drugs are given was brought up during a conversation at the 3rd American Association of Pharmaceutical Scientists/US Food and Drug Administration Bioanalytical Workshop but was not discussed at the meeting sessions. The purpose of this article is to discuss the challenges related to this issue and present a few approaches and experiences to elicit further discussions. Specificity and selectivity tests should be based on the anticipated levels of the individual therapeutics with reference to the dosing regimens defined in the clinical study protocol. When the concomitantly administered compound is available as a pure or well-defined material, various concentrations from zero to above the expected high levels are added to validation samples of the protein therapeutics to assess specificity. Recovery results from spiked samples of target patient populations on concomitant medications can also be compared with those from normal individuals for selectivity. If the drug has an endogenous counterpart, the baseline concentrations of each lot should be subtracted from the test samples in the selectivity assessment. This article illustrates a flexible approach to evaluating specificity and selectivity on samples from target patient populations receiving multiple medications.