Antibody drug conjugates (ADCs) have garnered much attention in the industry because of their combination of high selectivity and high potency. However, few have been approved and they remain incredibly challenging to develop and manufacture, not least because of the significant challenges involved in combining the right cytotoxic payload at the optimal sites on the antibody in the most efficient way. These challenges are becoming more acute because of the increasing number of best-in-class ADCs that incorporate inherently hydrophobic DNA-interfering payloads, such as pyrrolobenzodiazepines or duocarmycin payloads. DNA-interfering agents are of high interest to ADC developers because they do not rely on a specific part of the cell cycle, unlike other payloads used in ADCs, such as tubulin inhibitors (for example, auristatins and maytansines). Though the payload only constitutes two percent of the overall ADC composition, it can dramatically increase the propensity of the ADC to aggregate.
In my view, it is simply not possible, using conventional production techniques, to successfully commercialize ADC candidates that are optimized for both safety and activity. The biggest problem is that of aggregation, which is an inherent problem associated with conventional solution phase-based bioconjugations. Right now, few process-based aggregation control strategies are being used by industry; instead, companies try to address the problems by compromising on both ADC design (limiting drug to antibody ratios) and by modifying the payload design to improve solubility and “dilute” overall payload hydrophobicity. A number of other solutions have been proposed to tackle aggregation, but I believe we really need to deal with the problem at the source. For example, it is possible to prevent aggregation through immobilization before segregating individual antibodies during the critical conjugation phase. Following conjugation to the payload, the immobilized ADC product can be washed to remove excess payload and solvent (critical quality attributes for ADCs). Purified ADC is subsequently released from the solid-phase support into an optimal formulation containing stabilizing excipients that further suppress aggregation.
Increasing investments are being made in bioconjugation facilities within the biopharmaceutical sector – and a small number of specialist contract development and manufacturing organizations have also appeared. The industry is clearly keen to enhance ADC production, but we really need more focus on production techniques that can control aggregation – and, of course, techniques must be scalable to cope with production quantities. There are also other ways in which ADC development can improve. Firstly, researchers require much greater certainty: read-outs from initial in vitro panels must be accurate and reliable predictors of in vivo efficacy and safety in early stage ADC development. We need to guarantee that ADCs are free of residual contaminants – most importantly unconjugated cytotoxic payloads and solvents that have a negative impact on in vitro assays by exaggerating an ADC’s cell killing capability.
Secondly, we must consider cost. The risk of loss of high-value components, including the antibody and the cytotoxic payload to aggregation and associated loss of yield, must be minimized. Once materials are lost to aggregation they are no longer recoverable and ADC production can quickly become too uneconomical to carry out. We should perhaps consider reducing the number of process steps and focus on solving the critical issues of aggregation and poor removal of excess process reagents at source, thus avoiding the need for conventional purification equipment. Ultimately, we need more effective conjugation methods where product quality is paramount and where the process yield is optimized. Right now, there are long delays in the clinical development of ADCs, and decisions about candidate drugs tend not to focus on the biology but rather the manufacturability – a drug is no use if it cannot be made at scale. But this must change. The transformation is underway with emerging technologies and techniques – and we must keep the forward momentum going.
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