MONOCLONAL ANTIBODIES FOR IN VIVO APPLICATIONS - PART II 

Minerva Biotecnologica 1998 December;10(4)162-73

Copyright © 1998 EDIZIONI MINERVA MEDICA

lingua: Inglese

Antibody tergeted ribonucleases for cancer therapy

Rybak S. M. ¹, Newton D. L. ²

¹ Pharmacology and Experimental Therapeutics Section, Laboratory of Drug Discovery Research and Development, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick; ² Intramural Research Support Program, SAIC Frederick, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, USA

Targeted ribo­nu­cle­as­es are anti­body-­enzyme chi­me­ras in ­which the anti­body is ­either genet­i­cal­ly ­fused or chem­i­cal­ly ­linked to the ribo­nu­cle­ase. In ­this arti­cle we high­light ­both the RNase effec­tor and anti­body tar­get­ing ­domains ­with ­respect to ­their struc­ture and func­tion. Protocols for the con­struc­tion and pur­ifi­ca­tion of ­both chem­i­cal con­ju­gates and ­fusion pro­teins are ­described. RNases con­ju­gat­ed to sev­er­al anti­bod­ies via chem­i­cal link­ag­es exhib­it a 50 (Onconase) to 5000 ­fold (RNase A) ­increase in spe­cif­ic cyto­tox­ic­ity to ­tumor ­cells in ­vitro ­over the uncon­ju­gat­ed ­enzyme. Genetically engi­neered RNase ­fusion pro­teins ­designed ­with ­site spe­cif­ic link­ag­es are two to ­four ­logs (nM vs µM, respec­tive­ly) ­more ­potent ­than chem­i­cal con­ju­gates due to the inabil­ity to con­trol the ­sites of deri­vat­iza­tion and link­age in the lat­ter ­reagents. Due to ­lack of non-spe­cif­ic tox­ic ­side ­effects to nor­mal tis­sues effec­tive treat­ment con­cen­tra­tions are eas­i­ly achiev­able in ­murine anti­tu­mor mod­els. Continued advanc­es in the ­design, pro­duc­tion and func­tion of tar­get­ed RNases dem­on­strate ­that ­they are pro­gress­ing ­toward becom­ing a new ­class of anti­can­cer ther­a­peu­tics.