Figure 2

Possible mechanism(s) of action are shown for an ADC with a diffusible drug (MMAE) attached with a cathepsin B cleavable linker. The canonical processing pathway for an ADC involves (1) binding of the ADC to the target antigen and (2) internalisation. (3) The ADC is transported to the lysosome where the linker is cleaved, producing free diffusible drug (4). This free drug can then bind to microtubules (5) or DNA (depending on drug type) within the target cells to induce cell cycle arrest and ultimately result in cell death. The free drug can also diffuse out of the target cell (6) and penetrate surrounding ‘bystander’ cells to cause cell death. After ADC binding to the target antigen (7) but before internalisation, an alternative route for ADC processing is cleavage by extracellular enzymes (such as cathepsin B), which are released by surrounding tumour cells and tumour-associated macrophages (TAMs) and which generate diffusible drug from the ADC (8). This free drug can then penetrate surrounding ‘bystander’ cells resulting in cell death. Also, the ADC-bound target tumour cell may be internalised through Fc-mediated phagocytosis (9), which upon degradation of the target tumour cell would also result in release of free, diffusible drug (10).

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