A few decades ago, the pharmaceutical industry developed and commercialized racemic small molecule drugs. Despite the success achieved with racemic drugs, the risk associated with the use of an enantiomer not contributing to the therapeutic effect (but to side-effects, like in the thalidomide tragedy), combined with scientific and technical advances allowing manufacturing of enantiomerically pure drugs, have made this approach obsolete.[1]

Currently, a racemic small molecule drug is very unlikely to get FDA approval regardless of its therapeutic properties. It is equally unlikely that a pharmaceutical company would even try to develop such a therapeutic.[2]

Will the ADC community experience the same revolution?

Heterogeneous ADCs
The two commercial antibody-drug-conjugates, brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche), as well as a majority of clinical ADCs are a heterogeneous mixture of products that differ in the sites and stoichiometry of conjugation. Although they can offer improved treatments to some patient populations, heterogeneous ADCs suffer from a few drawbacks:

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  • The heterogeneity complicates manufacturing: batch to batch reproducibility is more difficult to achieve even if it can be mastered given the right equipment and know-how;
  • More complex analytical testing is required;
  • The individual compounds present in the ADC mixture do not have the same physico-chemical (e.g. aggregation) and pharmaceutical (pharmacokinetic profile and toxicity) properties, resulting in a suboptimal therapeutic treatment;
  • Higher DAR species present in the mixture are associated with faster clearance and increased toxicity.

Site-directed conjugation
The emergence of site-directed conjugation techniques gives access to ADCs with improved homogeneity. [3] Site-directed conjugation will not only allow manufacturing of more homogeneous ADCs with optimal drug loading, it will also (or maybe first) facilitate drug development. Controlling the drug loading and conjugation site allows a comparison between homogeneous candidates, providing new learning and making ADC development less empirical.

The author believes that site-directed conjugation will ultimately result in improved standards of care and become the new gold standard for bioconjugation. This provides opportunities for patients as well as for the pharmaceutical industry.

April 10, 2015 | Corresponding Author Laurent Ducry, Ph.D | doi: 10.14229/jadc.2015.4.10.001

Received: March 29, 2015  | Published online April 10, 2015 | This submitted editorial has not been peer reviewed.

Disclosures: Laurent Ducry, Ph.D is an employee of Lonza, one of the founding partners of ADC Review / Journal of Antibody-drug Conjugates.  He is also a member of the journal’s Editorial Advisory Board.

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Laurent Ducry, Ph.D
Laurent Ducry, Ph.D (born 1971) studied chemistry at the University of Lausanne (Switzerland) and did his diploma thesis with Prof. T. Gallagher at the University of Bristol (UK). He obtained his Ph.D. from the ETH Zürich (Switzerland) with Prof. F. Diederich in 1998. During his graduate studies, he worked during six months with Dr. G. Olson at Hoffmann-La Roche in Nutley (New Jersey). He then held a Swiss National Science Foundation postdoctoral fellowship at the University of Pennsylvania in Philadelphia with Prof. A. B. Smith, III and Prof. R. Hirschmann. Ducry began his industrial carrier in process R&D at Lonza in Visp (Switzerland) in 2000 and became project leader the following year. His activities focused on the development and scale-up of chemical processes, as well as the production of pharmaceutical intermediates and APIs under cGMP. In the second half of 2006 he trained the Lonza R&D team in Nansha (China) and was promoted Senior Research Associate in 2007. Since 2008, he is leading the antibody-drug conjugates R&D group of Lonza. He is the editor of “Antibody-Drug Conjugates: Methods and Protocols” (Springer, Humana Press, 2013) and a member of the Editorial Advisory Board of ADC Review / Journal of Antibody-drug Conjugates.