Characterization of a CC49-based single-chain fragment-beta-lactamase fusion protein for antibody-directed enzyme prodrug therapy (ADEPT)

Bioconjugate Chemistry
Ralph F AldersonVolker Schellenberger

Abstract

CC49 is a clinically validated antibody with specificity for TAG-72, a carbohydrate epitope that is overexpressed and exposed on the cell surface in a large fraction of solid malignancies. We constructed a single-chain fragment (scFv) based on CC49 and fused it to beta-lactamase (BLA). Following optimization of the scFv domain by combinatorial consensus mutagenesis (CCM) for increased expression and stability, we characterized the protein variant for binding, in vivo pharmacokinetics (PK), and antitumor efficacy. The fusion protein TAB2.5 possessed a similar binding specificity relative to the parent antibody CC49. TAB2.5 also showed prolonged retention (T(1/2) = 36.9 h) in tumor-bearing mice with tumor/plasma ratios of up to 1000. Preliminary evaluation of TAB2.5, in combination with a novel prodrug, GC-Mel, resulted in significant efficacy in a colorectal xenograft tumor model and supports the utility of the protein as an agent for tumor-selective prodrug activation.

References

Jan 26, 1996·International Journal of Cancer. Journal International Du Cancer·M VictorzonC Haglund
Feb 5, 2003·Bioorganic & Medicinal Chemistry Letters·Vivekananda M VrudhulaPeter D Senter

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Citations

Sep 27, 2006·Cancer Biotherapy & Radiopharmaceuticals·Huguette Albrecht, Sally J DeNardo
Aug 18, 2012·Protein Engineering, Design & Selection : PEDS·Daniel C OsipovitchKarl E Griswold
Aug 21, 2013·Journal of Nanobiotechnology·Syed AhmedEnoch Y Park
Feb 17, 2011·Immunotherapy·Carima AndradyKerry A Chester
Jul 4, 2012·International Journal of Molecular Sciences·Carmela Dantas-BarbosaAndrea Queiroz Maranhao
May 5, 2009·Biochemical and Biophysical Research Communications·Ryohei IwasakiHiroshi Ueda
Oct 16, 2016·Expert Opinion on Biological Therapy·Surinder K Sharma, Kenneth D Bagshawe
May 22, 2007·Trends in Biotechnology·Maneesh JainSurinder K Batra
Aug 10, 2010·Journal of Immunological Methods·Yoshiyuki SasajimaHiroshi Ueda
Oct 31, 2006·Expert Review of Anticancer Therapy·Kenneth D Bagshawe
May 23, 2009·British Journal of Pharmacology·Patrick ChamesDaniel Baty

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