Precision delivery: why tissue targeting matters more than potency

For most of drug development's history, the dominant strategy for a therapeutic that isn't working well enough has been to make it stronger: a higher-affinity binder, a more potent payload, a higher dose. That strategy has a ceiling, and the ceiling is toxicity. If a drug can't be concentrated specifically in diseased tissue, increasing potency just means increasing the damage done everywhere else the drug also happens to go.

There's a real example of what happens when you solve the other side of that equation instead. Pulmonary fibrosis is typically treated systemically — a therapeutic circulates throughout the body to reach diseased lung tissue, with the entire non-lung distribution counted as an acceptable cost of getting enough drug to the target organ. When an anti-TGF-beta bispecific antibody was engineered instead to pump directly into lung tissue via caveolae-mediated transport, it achieved therapeutic efficacy in a bleomycin-induced fibrosis model at an ultra-low dose (Kadam et al., PLOS ONE, 2022) — not because the antibody was more potent, but because nearly all of the dose that mattered ended up where the disease was, instead of being diluted across the entire circulation.

The tumor-targeting data tells the same story with different numbers. An antibody engineered against truncated Annexin A1 doesn't outperform non-targeting antibodies because it's a better binder in isolation — it outperforms them because it reaches roughly 15% injected dose per gram in tumor tissue, over 100 times the concentration of a non-targeting antibody, while normal organs see under 1% (Oh et al., Nature Medicine, 2014). That gap between on-target and off-target concentration is the entire therapeutic window. Potency didn't create it. Delivery did.

This is precisely why "how strong is the payload" has never been the hardest question in drug discovery — "how do you get an acceptable amount of any payload specifically into diseased tissue" is. A weaker drug delivered with high tissue specificity can outperform a far more potent drug delivered indiscriminately, because the therapeutic index is a function of concentration at the target, not concentration in a test tube.

Why this reframes what "a good target" means

If tissue specificity is what actually determines whether a therapeutic works safely, target discovery has to score for it directly, rather than treating it as a downstream formulation problem. That's the premise AVATAR is built on: every candidate is ranked not only for disease association, but for whether a therapeutic aimed at it can be concentrated specifically in the tissue that matters, using a validated, active transport mechanism. Treat delivery as a first-order scoring criterion, not an afterthought, and the definition of "a good target" changes — and so does what makes it into a preclinical pipeline in the first place.

Read the original research: Kadam et al., PLOS ONE (2022) · Oh et al., Nature Medicine (2014)