As an industrial pioneer in antibody-drug conjugate (ADC) development, Creative Biolabs offers customarily tailored ADC preparations with a variety of DNA-targeting toxins as payloads, including calicheamicins, doxorubicin, duocarmycin analogs, PBD-dimers, topotecan, bleomycin A2, dactinomycin, and mitomycin C.
DNA toxins
As one of the most fundamental bio-macromolecules, DNA is the carrier of the genetic information that governs all subcellular activities. Agents interfering with DNA structural integrity or the transcription machineries always lead to catastrophic effects on cell physiology and subsequently lead to cell death, making them ideal candidates for cancer chemotherapy and ADC development.
DNA damage caused by DNA toxins. Left: the crosslinking of double-stranded DNA by an analogue of PBD dimers at specific nucleotide sites (Cancer Res., 2010). Right: some DNA toxins induce oxidative DNA cleavage (Nat. Prod. Rep., 2010).
DNA toxin bases ADCs
DNA toxins are widely used in conventional cancer chemotherapies. However, several biophysical and biochemical features of those toxins, including high cytotoxicity, poor water solubility, high serum stability… affect their efficacies and result in a narrow therapeutic window. Developing into an ADC can circumvent some of those shortcomings. So far, a few DNA cleavers, DNA intercalators, and DNA topoisomerase poisons are under active development to form highly potent ADCs for efficient drug delivery and accurate target elimination. In one case, N-acetyl gamma calicheamicin dimethyl hydrazide (CalichDMH) was conjugated to a humanized anti-CD33 IgG4 κ antibody via a 4-(40-acetylphenoxy) butanoic bifunctional linker, resulting in an acyl hydrazine linkage between the payload and antibody and a drug to antibody ratio (DAR) of around two to three. Meanwhile, ADCs containing powerful DNA crosslinking pyrrolobenzodiazepine (PBD) dimers have also been developed into clinical evaluations.
With our deep understanding of drug and linker chemistry and our advanced synthetic chemistry “DrugLnk” service platform, Creative Biolabs offers high quality customarily tailored ADC development service using DNA toxins as payloads. Our services include, but are not limited to linker design, synthesis of the drug-linker set, antibody conjugation, and ADC biochemical analysis. Please contact us for more information and a detailed quote.
References:
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