AZ13601508 is one of AstraZeneca’s antibody drug conjugate (ADC) payloads based on the tubulysin natural products. We have scaled-up the synthesis of AZ13601508, manufacturing multiple batches on a 100g scale. The key challenges to making this molecule are: quality; synthetic complexity; toxicity; high cost; and long lead times. To meet these challenges, we applied both route design and process design, developing a synthetic route to the hexapeptide using solid phase peptide synthesis (SPPS). We established new routes to the tubuvaline and tubuphenylaniline portions of the molecule, whilst optimising the SPPS to increase yield and robustness. We have increased the yield of the synthesis 320-fold (0.01% to 3.2%) whilst reducing the number of liner steps from 21 to 19. We are currently further improving the route to reduce the amount of high containment manufacturing required.

Challenges and opportunities in the synthesis of ADC payloads

256th National Meeting (2018)

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