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IT-101:
CYCLOSERT™-ENHANCED CAMPTOTHECIN
Calando’s lead drug candidate, IT-101, is comprised of Cyclosert™ in combination with the anticancer compound camptothecin for systemic treatment of cancer. A natural compound found in the bark of the Chinese Camptotheca Acuminata tree, Camptothecin has potent anticancer properties against a broad spectrum of tumor cell lines. Its method of action inhibits the enzyme topoisomerase 1, which is key to the winding and unwinding process of DNA that is an essential step in cell division and replication. Interrupting this process prevents DNA replication and leads to cell death.
IT-101 was designed to harness the anticancer properties of camptothecin while overcoming its pharmacological shortcomings. First, camptothecin is virtually insoluble in water, making any sort of systemic application difficult. Second, at human blood pH levels, it rapidly hydrolyzes from its active lactone form to its carboxylate form, which remains highly toxic, but lacks anticancer properties. Finally, in its carboxylate form camptothecin has a high binding affinity with human blood proteins in vivo which prevents the camptothecin from eventually equilibrating between its active and inactive forms. All of these properties dramatically reduced its efficacy and increased its toxicity in humans compared to results obtained in animal testing.
The components of IT-101 are ß-cyclodextrin (“CD” in the figure below) and polyethylene-glycol (“PEG”), both of which are used in a variety of drug formulations, and L-cysteine, a natural amino acid. Camptothecin is covalently attached to Cyclosert™ through a glycine linker. Covalent coupling increases the water solubility of camptothecin by greater than 1000-fold and stabilizes it in its active lactone form. After intravenous infusion of the IT-101 nanoparticles, camptothecin is slowly released form the polymer-drug conjugate through hydrolysis of an ester linkage.
Structure of IT-101. m = number of repeating units of (Cyclosert™-Camptothecin) in the IT-101 conjugate (average m = 14 ± 4 for parent polymer Mw of 48 – 85 kDa). |
EFFICACY STUDIES
Efficacy studies were performed in mice bearing different subcutaneous xenograft tumors and in a disseminated tumor model of Ewing’s sarcoma. The results of some of these studies are summarized in the graphs and photographs below:
IT-101 Efficacy Studies. Median tumor growth curves for untreated animals (diamonds), animals dosed with irinotecan (squares), or IT-101 (triangles) in six different xenograft models in nude mice. Irinotecan was dosed IP on days 0, 7, and 14, 100mg/kg, and IT-101 IV (tail vein injection) on days 0, 7, and 14 at 16.1mg/kg for LS174T (colon cancer), H69 (small-cell lung cancer), H1299 (non-small-cell lung cancer) and MDA-MB231 (breast cancer), and 12.9mg/kg for HT29 (colon cancer) and Panc-1 (pancreatic cancer).
Ewing’s Sarcoma Efficacy. Efficacy of irinotecan (top panel) and IT-101 (bottom panel) in a disseminated TC71-luc (Ewing’s Sarcoma) tumor model in NOD/SCID mice (numbers across top of panels indicate days before, or following, initial treatment). Complete remission was achieved with IT-101 treatment. Tumor burden was monitored using a Xenogen imaging system. Mice were treated on days 0, 7 and 14. Mice were dosed with irinotecan IP at 100mg/kg, and with IT-101 IV (tail vein injection) at 12.5mg/kg. |
IT-101 showed significantly enhanced antitumor efficacy compared to irinotecan alone in all tumor xenograft models tested. In two models (Ewing's sarcoma and non-small lung cancer), complete remission was achieved. Preclinical results indicate that administration of IT-101 results in reduced toxicity and increased antitumor efficacy compared to both campothecin and irinotecan. These results prompted Calando to initiate clinical development of IT-101 as an anticancer agent.
CLINICAL DEVELOPMENT PLAN
For information about Calando Pharmaceuticals’ clinical trials please see our “In the Clinic” page
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