Prodrug-C-DOX

Creative Biolabs offers the best C-DOX as a prodrug for comprehensive antibody-β-lactamase conjugate-based ADEPT development services in cancerous biotherapy. Relying on the outstanding academic group and profound expertise, we have successfully established an advanced ADEPT system that can be utilized to evaluate the prodrug potential for a broad range of tumor treatment candidates.

C-DOX

C-DOX (Cephalosporin-doxorubicin) is a cephalosporin-based prodrug of doxorubicin which could efficiently release doxorubicin in the presence of an immunoconjugate consisting of a β-lactamase-MAb. Doxorubicin is a potent chemotherapy medication generally used in some leukemias and Hodgkin's lymphoma treatment, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, and others. Treatment with prodrug C-DOX resulted in a significant cytotoxic activity that was comparable to the parent drug doxorubicin. Thus, C-DOX can be developed as an anticancer prodrug combining with a monoclonal antibody-enzyme conjugate.

MOA of C-DOX

The β-lactamases enzyme catalyzes the cleavage of prodrug C-DOX (Cephalosporin-doxorubicin) and thus creates effective drug doxorubicin, which is a chemotherapy medication used to treat cancer. Doxorubicin is a potent DNA crosslinking agent which can interact with DNA by intercalation and inhibition of macromolecular biosynthesis. It inhibits the move of topoisomerase II, an enzyme which relaxes supercoils during DNA transcription. Doxorubicin can stabilize the topoisomerase II complex after it has broken the DNA chain for replication.

Fig.1 Translocation of prodrug across plasma and nuclear membrane of breast cancer cells. (Ray, 2016)

C-DOX-based ADEPT

The use of reactive C-DOX (Cephalosporin-doxorubicin) prodrug for ADEPT may prove advantageous because the generated drug will be highly cytotoxic. ADEPT using C-DOX as prodrug is under active development for a long time. The humanized anti-p185HER2 antibody (humAb4D5-8) against the p185HER2-overexpressing breast cancer was used as a building block to engineering a disulfide-linked Fv (dsFv) β-lactamase fusion protein, which is used in antibody-dependent enzyme mediated prodrug therapy. The dsFv3-β-lactamase fusion protein produced from E. coli efficiently activates a cephalothin doxorubicin prodrug. PRODOX is about 20-fold less toxic than free doxorubicin against breast tumor cells lines SK-BR-3 and MCF7, which express p185HER2 at elevated and normal levels, respectively. Pretreatment the dsFv3-β-lactamase fusion protein specifically boosted the toxicity level of PRODOX to that of doxorubicin against SK-BR-3 but not MCF7 cells. The dsFv3-β-lactamase complex retains both antigen-binding plus kinetic activity in murine serum and is cleared rapidly in nude mice. Development and characterization of the dsFv3-β-lactamase fusion protein is a promising therapy of p185HER2-overexpressing tumors.

Fig.2 Targeted cancer therapy using ADEPT. The ADEPT approach specifically aims at causing bystander effects by targeting enzymes to the tumour cell and delivering a prodrug that is converted to a chemotherapeutic by the targeted enzyme. (Schrama, 2006)

Based on advanced organic synthesis platform and experienced scientist team, Creative Biolabs offers C-DOX for the antibody-β-lactamase conjugate-based ADEPT development. Our tailored services and high-quality products will contribute greatly to the success of your projects. Any question about ADEPT development, please contact us for more information.

References

1. Ray, A.; et al. Doxorubicin prodrug for cytoplasmic and nuclear delivery in breast cancer cells. Drug Development and Therapeutics. 2016, 7(1), 13.
2. Schrama, D.; et al. Antibody targeted drugs as cancer therapeutics. Nature Reviews Drug Discovery. 2006, 5(2), 147-159.

For Research Use Only. NOT FOR CLINICAL USE.