Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model

Abstract

We recently reported on the in superior in vivo antitumor efficacy of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (INNO-206, formerly DOXO-EMCH), an albumin-binding prodrug of doxorubicin with acid-sensitive properties (see Fig. 1), in three tumor models in this journal, i.e. in three xenograft models (breast carcinoma M3366, ovarian carcinoma A2780, and small cell lung cancer H209) as well as in an orthotopic pancreatic carcinoma model (AsPC-1) [1] Previously, INNO-206 has shown significantly improved activity over doxorubicin in two xenograft breast cancer models and an orthotopic murine renal cell carcinoma model [2] and recently against resistant and non resistant myeloma (see http//:www.cytrx.com). INNO-206 binds rapidly to circulating serum albumin and releases doxorubicin selectively at the tumor site due to incorporation of an acid-sensitive hydrazone bond. The accumulation of INNO-206 in tumor tissue combined with a favorable biodistribution [3] is due to the pathophysiology of tumor tissue, characterized by a high metabolic turnover, angiogenesis, hypervasculature, a defective vascular architecture and an impaired lymphatic drainage, the so-called EPR (enhanced and retention) effect [4]. As a carrier for INNO-206, we selected albumin, which is emerging as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptideor protein-based drugs [5]. Albumin is a potential carrier for tumor targeting because it accumulates in solid tumors. In addition, we discovered that the HS-group of cysteine-34 of albumin is a unique and accessible functional group of a plasma protein for in situ prodrug conjugation considering that free thiol groups are absent from most circulating serum proteins except for albumin, which makes this group by far the most abundant thiol group in human plasma After injection directly into the blood stream, INNO-206 binds in situ to the cysteine-34 position of circulating albumin and is then transported in its albumin-bound form to the tumor site. INNO-206 is a prodrug of the anticancer agent doxorubicin in which doxorubicin is derivatized at its C-13 keto-position with a thiol-binding spacer molecule, i.e. 6-maleimidocaproic acid hydrazide. It contains an acidsensitive hydrazone linker that allows doxorubicin to be released either extracellularly in the slightly acidic environment often present in tumor tissue (pH range 6.0-6.8) [6] or intracellularly in acidic endosomal (pH 5.0-6.5) or lysosomal (pH 4.0-5.0) compartments after cellular uptake of the albumin conjugate by the tumor cell. INNO-206 was selected as an investigational product for clinical evaluation after toxicology studies in mice, rats, and dogs had shown a 2.5to 5-fold increase in the maximum tolerated dose (MTD) when compared to conventional doxoElectronic supplementary material The online version of this article (doi:10.1007/s10637-011-9686-5) contains supplementary material, which is available to authorized users.