Synthetic polymers conjugated to monoclonal antibodies: vehicles for tumour-targeted drug delivery.
(N-(2-Hydroxypropyl)methacrylamide (HPMA)) copolymers have seen extensive development as sophisticated lysosomotropic drug carriers. They can be used for site-specific drug delivery by incorporation of appropriate targeting groups and here we report their conjugation to antitumour monoclonal antibodies (the murine IgG, antibody B72.3 and its Fab' and Fab'2 fragments) and assessment as vehicles for tumour-specific drug delivery. Conjugates were synthesised containing an average 5 copolymer units (Mw 20kD) per antibody molecule. Kinetics of elimination and body distribution of radiolabelled conjugates in mice were substantially modified compared with native antibody and fragments, showing prolonged circulation in the bloodstream. Notably, the half-time for bloodclearance of the Fab' fragment (35min) was extended ten-fold following conjugation (6h). The conjugates provoked only a low immune response in A/J mice, following three injections in adjuvant (IgG titre-1 less than 100), and were resistant (up to 50%) to proteolytic degradation by preparations of rat liver lysosomal enzymes. The parent antibody targeted efficiently to human colorectal carcinoma (LS174T) xenografts in nude mice (up to 25%/g); the conjugates, however, showed no tumour-targeting, probably due to masking by polymer chains (which are attached by non-specific aminolysis). Conjugates designed to maintain immunoreactivity following linkage through oxidised carbohydrates are currently being synthesised. Nevertheless, the conjugates display increased rates of extravasation, compared with proteins of the same hydrodynamic size, and the decreased charge is anticipated to accelerate diffusion through tumour interstitium.
Seymour
L W
LW
Cancer Research Campaign's Polymer-Controlled Drug Delivery Group, University of Keele, U.K.
Flanagan
P A
PA
al-Shamkhani
A
A
Subr
V
V
Ulbrich
K
K
Cassidy
J
J
Duncan
R
R
D000178:Acrylamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000378:metabolism; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D000922:Immunotoxins / Q000008:administration & dosage* / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000201:enzymology; D009368:Neoplasm Transplantation; D010447:Peptide Hydrolases / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000178:Acrylamides; D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D010447:Peptide Hydrolases; C032976:N-(2-hydroxypropyl)methacrylamide