Manufacturing assessments critical in ADC development, says AZ

Manufacturing is key to bringing ADCs to the clinic faster says AstraZeneca, which stresses the importance of carrying out developability assessments.

When a new molecule enters AstraZeneca’s portfolio, one of the first things the Anglo-Swedish biopharma firm does is carry out a developability assessment to understand the challenges in bringing the candidate through the clinic.

Like other drug developers, the firm has a series of processes to move a project from lead optimization to candidate profiling, before moving into the preclinical phase.

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“At this stage we have to start incorporating a manufacturability assessment,” Michaela Wendeler, principal scientist, Biopharmaceutical Development at AstraZeneca, told delegates at Biotech Week Boston in September. This includes assessing “the ‘purifiability,’ the titer of the molecule, how well it fits the platform process, and how it responds to stresses during manufacturing,” she added.

“This assessment is important for all biologics but for antibody-drug conjugates even more so, simply because the cost of goods, the cost of development, is considerably higher.”

Antibody-drug conjugates (ADCs) consist of a monoclonal antibody, or antibody-fragment, used to deliver a payload to a tumor target. The payload itself consists of a highly potent warhead and a linker. Therefore, the complexity of an ADC, Wendeler said, is threefold that of a traditional biologic.

“From a CMC perspective it means we have three manufacturing GMP processes, for the antibody, the linker and the ADC – we file three distinct models for regulatory submissions, and due to variability, we need to select three lead molecules.”

Developers need to “start with the end in mind,” she continued, with a list of critical quality attributes (CQAs) for ADCs including drug-to-antibody ratio (DAR), drug load profile, and residual free drug, all of which have tight specifications due to the high potency involved.

Therefore, carrying out the manufacturability assessment is vital for ADCs, and having a rapid screen to assess viability is valuable to bring the molecule faster to the clinic to focus resources, she added.

“[We] need ultra-scale-down models to assess impact of physical stress and forces during processing… and then of course need to create a very integrated approach and need to combine all these assessments including stability and biophysical into one overall score.”

Trastuzumab deruxtecan

AstraZeneca has brought several ADCs to the clinic. Earlier this month, the US Food and Drug Administration (FDA) accepted the submission of breast cancer candidate trastuzumab deruxtecan – developed in partnership with Daiichi Sankyo – under priority review.

“Trastuzumab deruxtecan has the potential to transform the treatment landscape for patients with HER2-positive metastatic breast cancer who have limited treatment options today,” said José Baselga, EVP of Oncology R&D at AstraZeneca.

“This Priority Review draws on the strength and the consistency of results seen in the Phase I and Phase II trials and is a critical step on the journey to deliver this potential new medicine to patients.”