Figure 1. Inverse targeting strategy to reduce ADC toxicity associated with free payload.

(A) Major uptake mechanisms for ADCs and cytotoxic payloads. ADCs are internalized into targeted cells by receptor mediated endocytosis, and the drug linker is catabolized within the lysosomal space releasing the payload. Free payload can diffuse out of targeted cells, or cells that non-specifically degrade ADC, and into untargeted healthy cells resulting in off-target toxicities. (B) Proposed “inverse targeting” strategy to block off-target toxicity related to free payload exposure. Payload-binding agents (e.g., single domain antibodies, sdAb) bind and “neutralize” released payload in extracellular fluid (e.g., plasma), blocking diffusion of released payload across plasma membranes of untargeted cells, while not interfering with the receptor-mediated endocytosis of ADCs by targeted cancer cells.