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Targeted Drug Delivery

Targeted Drug Delivery


Mouse Studies Xenografts

Mice bearing tumors derived from a lung cancer cell line (A549) were treated with 1 x 109 EDVs™ per dose (black arrowheads indicate days on which mice were treated, as indicated on the x- axis). EDVs were either targeted to the epidermal growth factor receptor (EGFR) on the cancer cells (EGFREDV) or untargeted (EDV™) and loaded with the chemotherapeutic drug doxorubicin (EGFREDVDox; EDVDox) or paclitaxel (EGFREDVPac; EDVPac). Error bars indicate ± s.e.m, with 5 mice per treatment group.

Rhesus Monkey

Dog Studies – Endogenous Tumors

Stage 4 cancer in the brain of a dog (left image; white mass shown by yellow arrow). After 5 intravenous doses of EGFR-targeted, doxorubicin-packaged EDVs (one dose per week), the tumor completely disappeared (right image).

EnGeneIC has evaluated the safety and efficacy of EGFR targeted, doxorubicin loaded EDVTM nanocells (designated EGFREDVsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers.

EGFREDVsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI).  Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFREDVsDox (30 to 98 doses administered in 10 of the 17 dogs).

These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded EDVs™ for the effective treatment of patients with brain cancer.

The manuscript is currently under peer review with a scientific journal.

Safety Studies in Primates

Rhesus macaque monkeys were selected for non-clinical safety evaluation of EDVs™. In general, non-human primates are considered relevant models for preclinical research as they share a high degree of genetic homology with humans, underlying physiological and biochemical similarities between the species.

Three rhesus monkey trials were performed to assess toxicity of empty EDVs™ (up to 2 x 1010 per dose), EGFR-targeted doxorubicin-loaded EDVs™  (up to 2 x 1010 per dose), and EGFR-targeted paclitaxel-loaded EDVs™  (up to 1 x 1011 per dose).  Monkeys were treated with EDVs™ once weekly for 5 weeks (35 day repeat dose testing). There were transient spikes in temperature (increases of up to 1°C) with concomitant but self limiting elevation of IL-6 post-dose. The inflammatory marker C-reactive protein was also increased at these times, however no significant toxicities or adverse events were observed. A mild elevation of TNF-α was seen over the course of treatment with EGFR-targeted, doxorubicin-loaded EDVs™ only.

With regards to the bacterial component of EDVs™, it has been shown that rhesus monkeys mount an anti-LPS immune response through similar mechanisms to that seen in humans. Monkeys developed anti-LPS antibodies with EDVs™ treatment, but in general this response was mild and plateaued after approximately 3 doses.