Target occupancy — how you define it can make or break your drug
A drug can hit 100% “target occupancy” and still fail. Here's why.
For soluble targets at low concentrations (think cytokines), the usual PD assay is total target. If two ascending doses show no further accumulation, it's tempting to call the target saturated.
But when an antibody targets a cytokine, the antibody's half-life is usually longer than the target's — so binding "stabilizes" the target, and total target accumulates above baseline. That accumulation proves binding is happening. However, it doesn't prove free target has dropped enough for a therapeutic effect.
Target occupancy = bound target / total target. The saturated accumulation level (relative to baseline) is roughly set by the ratio of the drug-target complex half-life to the target's own half-life. If your complex's half-life is 100x the target's, occupancy approaches 100%, while telling you almost nothing about how much free target actually dropped. And free target reduction is the effect you're actually chasing.
So what does this mean for clinical strategy? It depends on whether a free-target assay is even feasible — post-dose, free target may be too low to measure reliably. Total target is still useful: with the right PK/PD model, it can reveal real information about the target. But it isn't sufficient on its own to determine the right dose or the right outcome.
Free target reduction is the outcome that matters.
Some references in the first post below
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A non-exhaustive list of references for a deeper dive:
Stein, A. and Ramakrishna, R. https://doi.org/10.1002/psp4.12169
Dua P, Hawkins E, van der Graaf PH. doi: 10.1002/psp4.41
Kapitanov et al., doi: 10.3389/fbinf.2021.731340 — "Right Dose" section.
Agoram BM. doi: 10.1111/j.1365-2125.2008.03297
Lowe, P.J., et al. https://doi.org/10.1111/j.1742-7843.2009.00513.x
Chimalakonda AP et al. doi: 10.1208/s12248-013-9477-3.
Davda JP, Hansen RJ. doi: 10.4161/mabs.2.5.12833.
Mager DE, Jusko WJ. doi: 10.1023/a:1014414520282.