Why PBD Dimers as ADC Payloads?
Introduction
The pyrrolobenzodiazepines(PBDs) are sequence-selective DNA minor-groove binding agents based on the naturally occurring anthramycin family of antitumor antibiotics.[1] Further, scientists found that joining two PBD units together via a flexible polymethylene tether allows the PBD dimers to efficiently cross-link opposing DNA strands producing highly lethal interstrand cross-links, and the activity of this PBD dimers reaches the pmol/L level in a variety of tumor cell lines.[2-3]
The PBD dimers were first studied as potential payloads for ADCs in a research collaboration between Spirogen Ltd and Seattle Genetics Inc in the mid to late 2000s. To date, there are more than 40 ADCs contained a PBD-based payload in pre-clinical/clinical stage.
Fig.1 The structure of PBD pharmacophore and PBD dimer
Structure-Activity Relationships of PBD Dimer
The skeletal structure of the PBDs contains a substituted aromatic A-ring, a diazepine B-ring and a pyrrolidine C-ring, with an S-chiral center at the C11a position between the B and C rings. Monomeric PBD units have been joined together through their C8/C8’-positions to afford PBD dimers.
The summary of the key SAR features of PBD dimers is provided below. In general, the functionalization of A-ring, the unsaturation and substitution of C-ring and the modifications between two PBD units can affect the affect the DNA binding ability and cytotoxicity of PBD dimer.[4-8]
Fig. 2 Summary of structure-activity relationships for the PBD dimers. Modifications which enhance activity are shown in blue, and those which reduce activity in red.[9]
The Features of PBD Dimers as a Distinctive Payload
Fig.3 The main steps in the mechanism of action of PBD dimer-containing ADCs
(a) binding to antigen target on the cell surface.
(b) internalisation into the cell.
(c) trafficking to the lysosome where cleavage of the linker occurs to release the free PBD dimer.
(d) binding of PBD dimer in the minor groove of DNA to produce cytotoxic DNA damage.
(e) a cascade of cellular events leading to cell death.[3]
● High Potency & Concise Structure:High potency enabling ADCs to be constructed with lower drug-antibody ratios (DAR) and concise structure enabling PBD dimers can be made through robust and scalable synthetic routes compared to auristatins and maytansinoids.
● Long Persistence in Cell:Their persistence in cells due to evasion of DNA repair mechanisms[2]. This contributes to their potency, but also to their ability to affect slowly proliferating target cells.
● Efficient bystander cell killing[10]: It’s an important determinant of efficacy in solid tumors with heterogeneous cell surface target antigen expression.
● Novel mechanism of drug action in ADC arena:It’s exploiting a completely different cellular target to the tubulin inhibitor classes, and a different mode of DNA damage to other DNA interacting warheads such as calicheamicin.
Reference:
[1] J. Am. Chem. Soc. 1965, 87, 5791-5793.
[2] Cancer Res.2004, 64, 6693-6699.
[3] Expert Opin. Investig. Drugs 2011, 20, 733-744.
[5] J. Med. Chem. 1994, 37, 4529-4537.
[6] Pharm. Pharmacol. Commun. 1999, 5, 555-560
[7] Blood 2013, 122, 1455-1463
[8] Bioorg. Med. Chem. 2007, 15, 3041-3053
[9] Angew. Chem. Int. Ed. 2017, 56, 462-488
[10] Mol Cancer Ther. 2016, 15, 2709–2721.