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CURRENT ISSUETHE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING

A Journal on Nuclear Medicine and Molecular Imaging


A Journal on Nuclear Medicine and Molecular Imaging
Affiliated to the Society of Radiopharmaceutical Sciences and to the International Research Group of Immunoscintigraphy
Indexed/Abstracted in: Current Contents/Clinical Medicine, EMBASE, PubMed/MEDLINE, Science Citation Index (SciSearch), Scopus
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The Quarterly Journal of Nuclear Medicine 1998 December;42(4):242-9

MOLECULAR MANIPULATION AND PHARMACOKINETICS 

Improving mono­clo­nal anti­body phar­ma­cok­i­net­ics via chem­i­cal mod­ifi­ca­tion

Sharifi J., Khawli L. A., Hornick J. L., Epstein A. L.

From the Department of Pathology University of Southern California School of Medicine Los Angeles, California, USA

The aim of radio­im­mu­no­ther­a­py in treat­ing sol­id ­tumors is to tar­get ­tumor ­sites ­while spar­ing nor­mal tis­sues. This can ­best be ­achieved by ­using a mono­clo­nal anti­body (MAb) ­with ­high ­tumor ­uptake and rap­id clear­ance. Because MAbs are ­basic, pos­i­tive­ly ­charged pro­teins, and mam­mal­ian ­cells are neg­a­tive­ly ­charged, the elec­tro­stat­ic inter­ac­tions ­between the two can ­create high­er lev­els of back­ground bind­ing result­ing in low ­tumor to nor­mal ­organ ­ratios. To over­come ­this ­effect, inves­ti­ga­tors ­have attempt­ed to ­improve MAb clear­ance by ­using var­i­ous meth­ods ­such as sec­on­dary ­agents as ­well as chem­i­cal and ­charge mod­ifi­ca­tions of the MAb ­itself. The use of a sec­ond ­agent to ­remove the MAb ­involves ­using a bio­tin­y­lat­ed MAb fol­lowed by treat­ments ­with a mole­cule ­like avi­din. Charge mod­ifi­ca­tion can be accom­plished by con­ju­gat­ing a chem­i­cal moie­ty ­with a pos­i­tive, neg­a­tive or neu­tral ­charge to res­i­dues ­exposed on the sur­face of MAbs. Experimental ­results dem­on­strate ­that the low­er­ing of the iso­electric ­point by ­this meth­od cor­re­lates ­with a ­decreased clear­ance ­time and ­improved ­tumor tar­get­ing. Altering the phar­ma­cok­i­net­ic char­ac­ter­is­tics of ­intact MAbs ­with ­charge mod­ifi­ca­tion can ­improve ­their clear­ance ­times to ­rates sim­i­lar to ­those of MAb frag­ments. Several ­groups ­have report­ed on the ­effects of chem­i­cal mod­ifi­ca­tion ­using mole­cules ­such as dex­tran, PEG, lac­tose and bio­tin. Some of ­these mod­i­fied MAbs ­retain the anti­gen bind­ing spec­i­fic­ity of the par­ent mole­cule and ­have ­improved clear­ance char­ac­ter­is­tics ­from ­blood and oth­er ­organs. Hence, ­these meth­ods can be ­used to ­improve ­both the diag­nos­tic and ther­a­peu­tic poten­tial of MAbs by improv­ing the sig­nal to ­noise ­ratio and the abso­lute ­tumor accre­tion of MAb, respec­tive­ly.

language: English


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