Characterization of a CC49-based single-chain fragment-beta-lactamase fusion protein for antibody-directed enzyme prodrug therapy (ADEPT) |
| |
Authors: | Alderson Ralph F Toki Brian E Roberge Martin Geng Wei Basler Joshua Chin Regina Liu Amy Ueda Roanna Hodges Douglas Escandon Enrique Chen Tianling Kanavarioti Tessi Babé Lilia Senter Peter D Fox Judith A Schellenberger Volker |
| |
Affiliation: | Genencor International, a Danisco company, 925 Page Mill Road, Palo Alto, California 94304, USA. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|