Improving monoclonal antibody pharmacokinetics via chemical modification.
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.
Sharifi
J
J
Department of Pathology, University of Southern California School of Medicine, Los Angeles, USA.
Khawli
L A
LA
Hornick
J L
JL
Epstein
A L
AL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D019921:Biotinylation; D003911:Dextrans; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007785:Lactose; D009369:Neoplasms / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D055672:Static Electricity