Antibody-drug conjugates (ADCs)—monoclonal antibodies (mAbs) covalently linked to toxic agents are acknowledged and employed in the art as improved anticancer treatments. The combination of targeting specificity of mAbs with cytotoxic small molecules, allows for discrimination between malignant and normal tissues resulting in fewer toxic side effects exhibited by many conventional chemotherapies.
Currently, there exist only three FDA-approved ADCs available for cancer treatment. Two of the ADCs, Zevalin® and Bexxar®, comprise mAbs covalently attached to the radioisotopes Yttrium-90 and Iodine-131, respectively. These murine radiolabeled mAbs are used in the treatment of CD20-expressing B-cell lymphomas. The third FDA-approved ADC, Mylotarg®, consists of a humanized anti-CD33 monoclonal antibody conjugated to the DNA-cleaving enediyne antibiotic, Calicheamicin. To date, this is the only approved immunoconjugate possessing a cytotoxic organic molecule.
Recently, groups at the National Cancer Institute (NCI) reported on the preparation and evaluation of immunoconjugates composed of HERCEPTIN® (Trastuzumab) and the cytotoxin, Geldanamycin. Mandler, R., et al., Trastuzumab-Geldanamycin Immunoconjugates: Pharmacokinetics, Biodistribution, and Enhanced Antitumor Activity, Cancer Res. 64:1460-1467 (2004). Geldanamycin is a highly cytotoxic ansamycin benzoquinone antibiotic that exerts its cytotoxicity by binding to the protein chaperone heat shock protein 90 (hsp 90). The anticancer potential of Geldanamycin as a single chemotherapeutic agent has been abandoned as a result of its nonselective and severe toxicity. Geldanamycin is unique in that targeting of hsp90 is effective at down-regulating HER2, and thus tumor cells that over express HER2 are especially sensitive to Geldanamycin. Trastuzumab-Geldanamycin was shown to have IC50s 10-200-fold lower than that of unmodified Trastuzumab in antiproliferative assays. In a xenograft murine model, consisting of weekly i.p. doses of 4 mg/kg over four months, animals treated with Trastuzumab-Geldanamycin exhibited 69% tumor regression, whereas those treated with Trastuzumab alone only showed 7% regression. Median survival time was 145 days as opposed to 78 days for Trastuzumab-treated animals. In addition, nearly one-third of the mice remained tumor free two months after treatment had been completed, whereas there were no survivors from the Trastuzumab group.
Nearly all organic anticancer agents are associated with dose-limiting toxicities. A significant need exists to improve drug efficacy while minimizing systemic toxicity while addressing optimization parameters, such as physiological barriers to targeting molecule extravasation and intratumoral penetration, immunonconjugate aggregation, immunogenicity, normal tissue expression of targeted antigens, and inefficient drug release from the carrier. Certain compounds, moreover, require an improved delivery system due to physicochemical properties such as water solubility, cellular uptake, as well as otherwise short half-life in vivo. Since prognosis of long-term, disease-free survival of most cancer patients remains poor, there continues to be a critical unmet need for improved anticancer treatment.