Pyrrolobenzodiazepines (PBDs)

Creative Biolabs has years of experience in antibody-drug conjugates (ADCs) development and we have established an advanced “DrugLnk” synthetic chemistry platform to serve this very purpose. We provide our clients with customarily tailored ADCs using pyrrolobenzodiazepine (PBD) or PBD-dimers as payloads via the most suitable linkers and conjugation strategies.

Pyrrolobenzodiazepines (PBDs) is a series of natural products derived from various actinomycetes that show strong anti-tumor or antibiotic activities. They are sequence-dependent DNA alkylating compounds and are proven to be more powerful than systemic chemotherapeutic drugs. As DNA minor groove binding agents, PBDs selectively cross-link specific DNA segments, hindering cell division and eventually lead to cell death. The non-discriminative working mechanism of PBD and PBD derivatives averts the usual phenomenon of emergent drug resistance, making them excellent candidates for anti-tumor therapies. Several dimeric PBDs (PBDs-dimers) have been used as cytotoxic drug payloads in ADCs, such as vadastuximab talirine, for acute myeloid leukemia (AML) treatment.

PBD mode of action (MOA)

PBDs bind the C2-amino portion of a guanine residue in a specific sequence configuration within the minor groove of double-stranded DNAs via their N10-C11 imine/carbinolamine groups. Covalent coupling of two PBD units via a pentyldioxy [-O-(CH2)5-O- diether] or a propyldioxy [-O-(CH2)3-O diether] linker at their C8 positions creates PBD dimers, which crosslink guanines on opposed DNA strands and result in DNA structural damage. Dimerization improve the sequence specificity, binding affinity, and drug effect of PBDs. Dimeric PBDs show good in vitro anti-tumor toxicity with IC50 values in the mid to low pico-molar ranges in several tested cell lines. Unlike anti-tubulin compounds, PBD and PBD dimers can cause cell death in both dividing and non-dividing status. High drug toxicity, abundant intracellular targets, as well as low tendency for drug-resistant development, the advantages of the natural or synthetic PBD and PBD dimers enable them to serve as good payload drugs for ADC development.

Pyrrolobenzodiazepines (PBDs) PBD dimer mode of action. PBD dimers bind to specially configured guanidine residues on different positions of the dsDNA helix and cause the crosslinking of DNA strands (Org. Biomol. Chem., 2015).

PBDs-based ADCs

A variety of PBDs and PBD-dimers have been synthesized and several of them have been incorporated in ADC development. SG-CD33A is an ADC under evaluation for AML treatment. The PBD-dimer in SG-CD33A is conjugated to a modified anti-CD33 antibody with engineered Cys residues through a small di-peptidyl linker. In another case, h1F6 239C-PBD is an ADC comprised of PBD dimers conjugated to an anti-CD70 antibody for renal cell carcinoma (RCC) treatment. Overall, the application of PBDs or PBD-dimers as ADC payload drugs is still under developed judging by the small volume of published records and it would be beneficiary to devote more attention to these highly toxic agents for the development of new generation ADCs.

Pyrrolobenzodiazepines (PBDs) Scheme showing the conjugation of PBD dimers to antibodies via engineered Cys residues to yield ADCs with a narrow drug to antibody ratio (Acta Pharm Sin, 2015).

With our well-established “DrugLnk” organic synthesis platform, the experienced scientists here at Creative Biolabs is dedicated to help our clients develop PBD/PBD dimer-linker complexes using suitable linkers for antibody conjugation in a timely and cost-effective manner. Our customarily tailored services and high quality products will contribute greatly to the success of your projects.

Creative Biolabs also provides other various services regarding ADC development. Please feel free to contact us for more information and a detailed quote.


  1. Sun, Y.; et al. Advances in the study of site-specific antibody-drug conjugates. Acta Pharm Sin. 2015, 50(10): 1225-1231.
  2. Jeffrey, S.C.; et al. A potent anti-CD70 antibody–drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology. Bioconjugate Chem. 2013, 24(7): 1256-1263.
  3. Rahman, K.M.; et al. Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates. J Antimicrob Chemother. 2012, 67: 1683 –1696.
  4. Thurston, D.E.; et al. Effect of hairpin loop structure on reactivity, sequence preference and adduct orientation of a DNA-interactive pyrrolo[2,1-c] [1,4] benzodiazepine (PBD) antitumour agent. Org. Biomol. Chem. 2015, 13: 4031-4040.

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