PDB-Dimer Payloads for Antibody Drug Conjugates: A Robust Approach to cGMP Production

From the 1960s when monomeric pyrrolobenzodiazepines (PBDs) such as anthramycin were isolated and characterized, to the dramatic increase of potency induced by dimerization in the 2000s, PBD dimers have evolved as one of the leading classes of antibody drug conjugate (ADC) payloads. Currently, 17 ADCs are in clinical trials involving PBD-dimers — second only to auristatins (23 ADCs), and more than those with maytansines (16 ADCs). Four different PBD-dimer ADC payloads are in clinical trials: Talirine (SGD-1910) from Seattle Genetics; Tesirine (SG3249) from Spirogen, MedImmune, ADC Therapeutics, and Abbvie; and DGN462 and DGN549 from Immunogen. With the most advanced PBD-ADC program, Abbvie- StemCentrx’ Rovalpituzumab-tesirine (Rova-T) closing to commercial launch, we summarize herein the production challenges and solutions presented by the PBD-dimer platform.

Several other companies also are involved in preclinical development of PBD-dimers ADC payloads, either through a license from Spirogen (Genentech, Mitsubishi Tanabe Pharma, Regeneron, and Gamamabs Pharma) or through proprietary internal payload development programs (Sanofi, Bristol-Myers Squibb, Cellerant Therapeutics, and Abzena).

PBD-dimers are DNA crosslinkers or alkylators. Upon ADC internalization and lysosomal processing, PBD-dimer payloads are released in the cytosol, then diffuse through the nuclear membrane and bind in the minor groove of DNA. After binding, the imine then can alkylate or crosslink the two DNA strands and block DNA replication. As shown on the computer-generated graphic (Figure 2), PBDdimer minor groove binding does not change DNA geometry, which makes this modification hard to identify and repair. PBD-dimer geometry is induced by the two H11a stereochemistries, so stereochemical control is absolutely necessary for biological activity.

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