Anti-Myeloma Effects of the Novel Anthracycline Derivative INNO-206

Abstract

Purpose: Doxorubicin has shown efficacy especially in combination treatment for the treatment of multiple myeloma; however, its side effects limit its use. INNO-206 is an albumin-binding prodrug of doxorubicin, which is released from albumin under acidic conditions. Because INNO-206 has not been previously evaluated in any hematologic malignancy, we determined its anti-multiple myeloma effects.Experimental Design: The anti-multiple myeloma effect of at different pH levels on multiple myeloma cell proliferation using multiple myeloma cell lines with the MTS assay and antiangiogenic activity using the chorioallantoic membrane/feather bud assay were determined. The anti-multiple myeloma effects and toxicity of INNO-206 were also compared with conventional doxorubicin and PEGylated liposomal doxorubicin (PLD) alone, and in combination with bortezomib, using our multiple myeloma xenograft models.Results: INNO-206 inhibited blood vessel formation and reduced multiple myeloma cell growth in a pHdependent fashion. INNO-206 alone produced marked anti-multiple myeloma effects in vivo at doses that doxorubicin was toxic, and the combination of INNO-206 plus bortezomib produced increased antimultiple myeloma effects compared with either agent alone. In contrast, all mice receiving bortezomib with doxorubicin or PLD died.Conclusions: These findings show that INNO-206 produces anti-multiple myeloma effects in vitro and in vivo. It also enhances the antitumor effects of bortezomib. These results suggest that INNO-206 may provide patients with multiple myeloma with an anthracycline that may be administered safely at higher doses compared with free doxorubicin, resulting in superior efficacy compared with the currently available anthracyclines to treat this B-cell malignancy.

Antitumour Anthracyclines: Progress and Perspectives

“…Further in vivo anti‐multiple myeloma effects and toxicity of 31 on mice with LAGκ induced tumour showed that a weekly dose of 10.8 mg/kg via intravenous administration (equivalent to 8.0 mg/kg of free doxorubicin) reduced extensively the tumour volumes between days 28 and 42 ( P =0.0152 to P =0.0036), whereas equivalent and lower doses of doxorubicin led to significant toxicity, resulting in the death of all animals by day 42 . This is consistent with previous reports about the diminished cardiotoxicity and mitochondrial impairments of derivative 31 , and consequent two‐ to fivefold higher lethal concentration as compared to doxorubicin .…”

“…In U266 cells, the acidic environment (pH 5) also increased the anti‐proliferative effect of 31 , but it was detrimental to the activity of free doxorubicin at all concentrations investigated, compared to results under physiological conditions tested at pH 7. Based on a chorioallantoic membrane/feather bud (CAM/FB) model, the antiangiogenic effects of 31 were also pH‐dependent, in agreement with early findings for anthracyclines, which showed inhibition of blood vessel formation due to reduced hypoxia‐inducible factor (HIF‐1) level in tumour cells …”

“…In turn, the acid‐labile hydrazone bond permits the release of doxorubicin under acidic conditions, such as in a tumour tissue environment and inside endosomes or lysosomes within tumour cells . Derivative 31 was also named DOXO‐EMCH„ INNO‐206 or aldoxorubicin …”

Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy

“…The on-going clinical studies suggest that INNO-206 can be administered safely at higher doses in patients than free doxorubicin, resulting in better efficacy compared with the currently available anthracyclines to treat several types of cancer. 188,190,191 …”

Protein based therapeutic delivery agents: Contemporary developments and challenges

“…In addition to DOX, HSA is able to bind its prodrugs (6-maleimidocaproyl)hydrazone (INNO-206, DOXO-EMCH), which exhibits better efficacy than DOX in numerous cancer models [35, 48, 49, 66, 67]. In a recent study of human pancreatic cancer cells, MIA PaCa-2, treated with the combinations of DOX and HSA-DOXO-EMCH, a 1:5 ratio of DOX to HSA-DOXO-EMCH has shown the highest synergistic profile in the cytotoxicity assay when DOX is introduced 6 hours prior to the addition of HSA-DOXO-EMCH [49].…”