Development of a novel anti-IGF1 receptor immunoliposomal cancer therapy with enhanced therapeutic efficiency
Constanze Hantel1, Felicitas Lewrick2, Sebastian Schneider2, Oliver Zwermann1, Martin Reincke1, Regine Peschka-Süss2 & Felix Beuschlein1
Overexpression and aberrant activation of the insulin-like growth factor system plays a key role in tumor cell proliferation and tumorigenesis in many human tumors. Different therapies targeting IGF1-receptor (IGF1-R) have been developed and currently, some of these agents are evaluated in preclinical and early clinical trials with promising results. Moreover, recent studies have demonstrated that combined treatments with doxorubicin, enhance the efficiency of anti-IGF1-R therapies. To merge these therapies in one formulation we coupled a monoclonal IGF1-R blocking antibody (1H7) to sterically stabilized liposomal doxorubicin (SSL-DXR). Flow cytometry analysis demonstrated high and significant cellular association of SSL-DXR-1H7 in comparison to SSL-DXR or unspecific IgG coupled SSL-DXR with human neuroendocrine tumor cells BON (44.2±1.6 vs 0.5±0.3 vs 0.8±0.3%; P<0.0001). Moreover, the lack of cellular association at 4°C together with visualization of intracellular fluorescence of 1H7 coupled rhodamine-PE labeled liposomes by fluorescence imaging verified the otherwise rarely achieved event of liposomal internalization after binding to the target cell. In vivo, pharmacokinetic experiments with BON tumor xenografts in NMRI nude mice confirmed increased doxorubicin accumulation in the tumors after treatment with SSL-DXR-1H7 (157±6%) in comparison to liposomes conjugated with unspecific IgG (100±18%, P<0.05). In a therapeutical study with large scale tumor bearing mice significant effects on mean survival time (days) were only detectable after treatment with SSL-DXR-1H7 (31.5±2.2; P=0.0084) in comparison to untreated controls (8.0±0.6) and compared with all other treatments (free 1H7, 20±0.8; P=0.0069; SSL-DXR-IgG, 20±1.4; P=0.0062; SSL-DXR, 22±1.8; P=0.0169; SSL-DXR + free 1H7, 23±2.4; P=0.0344). Further flow cytometry analyses (SSL-DXR-1H7 versus plain liposomes) with the tumor cell lines MCF7 (64.9±2.3 vs 0.04±0.1%; P<0.0001), Kelly (21.8±2.9 vs 0.02±0.009%; P=0.002) and DU145 (31.9±0.7 vs 0.06±0.02%; P<0.0001) indicate the suitability of the established therapy also for other human cancer entities as breast carcinoma, neuroblastoma and prostate carcinoma.