Antibody-carboxylesterases Conjugate

Creative Biolabs is a world’s leading service provider for antibody-directed enzyme prodrug therapy (ADEPT) development. Our expert team offers professional solutions and advanced technologies for antibody-carboxylesterases conjugate development, which will ensure the progress of our customers’ research.

Carboxylesterase

Carboxylesterase (carboxylic-ester hydrolase) is an enzyme can catalyze a carboxylic ester together with H2O to an alcohol and a carboxylate. Most enzymes are serine hydrolases with alpha /beta hydrolase fold. Carboxylesterases are broadly distributed in mammalian liver. Studies have shown that many carboxylesterases are involved in xenobiotics phase I metabolism such as toxins or drugs. Furthermore, carboxylates could conjugate with other enzymes to increase solubility and eventually excrete. A number of carboxylesterase proteins with different substrate specificities, such as acetylcholinesterases, have been discovered.

Crystal structures of human carboxylesterases. Fig.1 Crystal structures of human carboxylesterases. (de Souza, 2015)

MOA of Carboxylesterase

Carboxylesterase enzyme catalyzes the hydrolysis of prodrug CPT-11, which is known as Irinotecan (an analog of camptothecin-a topoisomerase I inhibitor) yielding parent drug SN38. SN38 is a potent antineoplastic drug. It is the active metabolite of irinotecan but has 1000 times more activity than irinotecan itself. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. Upon prodrug CPT-11 is administrated into the tumor site, the carboxylesterase can catalyze it to produce effective drug immediately to perform its cytotoxic effects.

Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Fig 2. Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. (Barthel, 2009)

Antibody-carboxylesterases Conjugate-based ADEPT

Antibody-directed enzyme prodrug therapy (ADEPT) has the potential to be an effective therapy for most common solid cancers. ADEPT using carboxylesterases as the enzyme is under active development and evaluation. An anti-p97 mAb 96.5 was linked to hCE-2, forming a conjugate that could bind to antigen-positive cancer cells and convert CPT-11 to SN-38. In vitro cytotoxicity experiments were performed on 3677 melanoma cells (p97 antigen positive). Cells were treated with the combination of 5 µg of 96.5-hCE-2/mL and CPT-11 for 24h. These results suggested that the enzyme within the conjugate is active and capable of activating CPT-11 under the conditions used in the cytotoxicity experiments. However, the amount of antigen-bound activity is too low to achieve detectable levels of prodrug activation. Thus, experiments were conducted with increased conjugate concentrations. Results shows that bound enzyme conjugates did not release cytotoxic concentrations of the active drug.

With our advanced technology platforms and experienced scientists for bio-conjugation projects, Creative Biolabs now provides custom antibody-carboxylesterases conjugate development service by using readily available or customized linkers or direct Antibody-enzyme fusion proteins. Our high-quality services and products will contribute greatly to the success of your projects. Please feel free to contact us for more information and a detailed quote.

References

  1. de Souza, V. A.; et al. Comparison of the structure and activity of glycosylated and aglycosylated human carboxylesterase 1. PloS one. 2015, 10(12), e0143919.
  2. Barthel, B. L.; et al. Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine. Journal of medicinal chemistry. 2009, 52(23), 7678-7688.


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