Synthetic Polymers Conjugated to Monoclonal Antibodies: Vehicles for Tumour-Targeted Drug Delivery

Abstract

(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.

Pegylation and Its Impact on the Design of New Protein-Based Medicines

“…HPMA was recently conjugated to the Fab′ and Fab′ 2 fragments of the B72.3 murine IgG. The resulting HPMA Fab′ conjugate displayed a 10-fold improvement in circulation half-life (from 35 min to 6 h) and a reduced immunogenic response but no anti-tumour activity due to the non-specific nature of the conjugation and the associated steric hindrance [176]. To maintain the biological activity, attempts have been made to link active substances to HPMA via hydrolytically labile spacers that are capable of releasing the fully active drug at low pH [177].…”

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies

“…Simple monosaccharide or oligopeptide targeting moieties as well as more complex polyclonal and monoclonal antibodies (Ab) or Ab fragments targeting T-lymphocytes, 297 transferrin receptor, 298 or human colorectal carcinoma 299 were attached to carriers using an aminolysis reaction in which reactive ester groups on a polymer precursor were aminolyzed by primary amino groups on the ligands. One of these Ab-targeted conjugates, a conjugate of P(HPMA) with the photosensitizer chlorin e 6 (mesochlorin), was used to assess the concept of double-targeted anticancer agents.…”

Next generation protein‐polymer conjugates

“…Work is currently being performed to improve the clinical efficiency of these therapeutics and several are on the market including, but not limited to, cetuximab, trastuzumab, and rituximab . Polymer conjugation to antibodies alters their function and studies have been performed in order to increase their therapeutics effectiveness through site‐specific conjugation strategies, targeted drug delivery, pH responsiveness, and self‐assembly into ordered antibody arrays . Other reports have specifically covered antibody‐polymer conjugates and full discussion is beyond the scope of this Perspective, but the synthesis and application of antibody‐polymer conjugates is highly paralleled with other therapeutic protein‐polymer conjugates.…”