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

Doxorubicin and pegylated liposomal doxorubicin have recently shown efficacy for the treatment of multiple myeloma (MM). However, the efficacy of these drugs as single agents and in combination therapies is limited by their myelosuppressive, cardiac and dermatological side effects. INNO-206 (CytRx Corporation, Los Angeles, CA) is an albumin-binding prodrug of doxorubicin that is released from albumin under acidic conditions. The bone marrow of MM patients is often acidic due to the increased activity of osteoclasts that allow free doxorubicin to be released from INNO-206. Following intracellular uptake, the drug is released in the acidic endosomal or lysosomal compartments. Thus, this drug offers the possibility of achieving higher levels of active doxorubicin near and within tumor cells than with conventional doxorubicin. Our laboratory has previously evaluated this compound in vivo using one of our SCID-hu MM models of MM and determined the anti-MM effects and toxicity of INNO-206 (10.8 mg/kg) alone when compared to conventional doxorubicin (4 and 8 mg/kg), both administered weekly via intravenous (i.v.) injection, using our severe combined immunodeficient (SCID) murine model of human MM, LAGk-1A. INNO-206 was able to be administered safely at much higher doses than conventional doxorubicin, and this novel anthracycline showed excellent anti-MM effects. However, the optimal dose and schedule of INNO-206 was not determined. Thus we set out to determine at what dose and schedule INNO-206 would provide the highest anti-MM activity with the lowest amount of drug using two of our MM xenograft models (LAGk-1A, LAGk-2).

Each SCID mouse received a 20 – 40 mm³ MM tumor piece surgically implanted into the left hind limb superficial gluteal muscle. Seven days post-implantation mice were bled, human IgG levels were measured by ELISA and mice randomized into treatment groups. INNO-206 stock solution was prepared using 50% ethanol and 50% water, and diluted to the appropriate dose in water. It was administered to LAGk-1A-bearing SCID mice at 5.4 mg/kg once weekly and 1.8 mg/kg thrice weekly via i.v. injection. Mice were bled for hIgG levels and the intramuscular tumors were measured using standard calipers on a weekly basis. Data was analyzed as the mean ± SEM. These studies were conducted according to protocols approved by the Institutional Animal Care and Use Committee.

SCID mice bearing LAGk-1A treated once weekly with INNO-206 at 5.4 mg/kg showed markedly smaller tumor volumes on day 56 compared to vehicle-treated mice (P = 0.0413). At day 56 post tumor implantation, 9/10 control mice were alive versus 8/10 mice alive in the 5.4 mg/kg INNO-206 group. In contrast, we also evaluated INNO-206 at 1.8 mg/kg administered thrice weekly (dose equivalent to 5.4 mg/kg INNO-206 once weekly), on consecutive days, which resulted in moderate tumor volume growth inhibition but not statistical significance. Additionally, we evaluated various doses and schedules of INNO-206 (0.9 mg/kg-10.8 mg/kg) in the LAGk-2 tumor and significant inhibition of tumor volume growth was observed two weeks into treatment with INNO-206 alone and in combination with bortezomib when compared to vehicle treated mice.

We have shown that the novel anthracycline INNO-206 shows marked anti-MM effects in vivo using our SCID-hu MM models LAGk-1A and LAGk-2. The results from these studies suggest that this doxorubicin conjugate may provide MM patients with a new anthracycline that may be able to be administered at higher doses safely resulting in superior efficacy compared to the currently available anthracyclines to treat this B-cell malignancy.

Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding.