Abstract P3-14-09: Preclinical Safety and Activity of MM-302, a HER2-Targeted Liposomal Doxorubicin Designed To Have an Improved Safety and Efficacy Profile over Approved Anthracyclines

Abstract

Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and ledto the exploration of anthracycline-free regimens, particularly with HER2- positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clearcut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2- overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. Materials and methods: MM-302, untargeted pegylated liposomal doxorubicin (PLD), and free doxorubicin were compared for their uptake into target and nontarget cells, pharmacokinetics, biodistribution, tumor microdistribution using FACS and confocal microscopy, and anti-tumor activity in BT-474 and NCI-N87 xenograft models. Results: Cellular uptake studies in tumor cell lines expressing various levels of HER2 demonstrate that MM-302 delivers significantly higher doxorubicin levels to HER2 over-expressing tumor cells compared to PLD as well as similar or higher levels than highly permeable free doxorubicin. However, in human cardiomyocytes, while free doxorubicin was again taken up at high levels, doxorubicin uptake was dramatically lower with both MM-302 and PLD. Pharmacokinetic studies in mice demonstrate that MM-302 has a similar half life, clearance, and organ distribution compared to PLD. In HER2-overexpressing BT-474 breast and NCI-N87 gastric tumor xenografts, MM-302 exhibits superior anti-tumor activity to both free anthracyclines and PLD. Tumor microdistribution studies further suggest that differences in the localization of doxorubicin in the tumor may be responsible for the enhanced activity of MM-302 compared to free doxorubicin and PLD. Discussion: These preclinical data suggest that MM-302 may provide in clinical practice a new opportunity to specifically deliver an anthracycline to HER2-overexpressing tumors with a potentially cleaner safety profile and improved efficacy over currently available free or liposomal doxorubicin. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-09.

Complex Effects of Tumor Microenvironment on the Tumor Disposition of carrier-mediated Agents

“…MM-302, currently in early phase clinical studies, incorporates anti-HER2 scFv-PEG-DSPE conjugates to the outer surface of PLD [29]. In preclinical models, MM-302 has shown superior antitumor activity to SM doxorubicin and PLD in HER2 over-expressing tumors [30].…”

The Effects of Nanoparticle Drug Loading on the Pharmacokinetics of Anticancer Agents

“…In preclinical models, MM-302 has shown superior antitumor activity to free doxorubicin and PLD in HER2 overexpressing tumors with a pharmacokinetic profile similar to that of PLD. In addition, MM-302 expressed a favorable cardiosafety profile compared with free doxorubicin [22]. …”

Biobetters

“…Glycosylation and PEGylation of therapeutic proteins are among the more wellstudied modifi cation for engineering protease-resistant peptides (Raju and Scallon 2006 ;Park et al 2010 ). Some of the more novel approaches include the generation of macrocyclic peptides by converting linear peptides into stable macrocycles via allylic substitution catalyzed by palladium (Lawson et al 2013 ), adding interchain disulfi de bonds to stabilize a coiled coil peptide structure (Tong et al 2013 ), and covalently crosslinking hydrocarbons across peptide regions to stabilize α-helical structures (Bird et al 2010 ;Braun et al 2010 ).…”

“…There are several approved products on the market that are PEGylated versions of their native molecule, including growth hormones, insulin, interferons, G-CSF, and L -asparaginase. PEG moieties are usually attached to the protein using N -hydroxysuccinamide or aldehyde chemistry and pH modulation (Park et al 2010 ;Clark et al 1996 ;Luxon et al 2002 ;Wang et al 2010 ). An advantage of the PEGylation chemistry is the ability to attach the PEG polymer to reactive amino acids such as an unpaired cysteine.…”

“…This may explain why, despite their fl ourishing in biomedical research for more than 25 years, no scFv has been approved as a biopharmaceutical to date . The currently most advanced scFv under clinical development (beside an immunotoxin fusion protein discussed below) is a PEG-linked conjugate with doxorubicin-charged liposomes targeting HER2, MM-302 (Merrimack, http://merrimackpharma.com ), that has entered phase II/III studies for the treatment of breast cancer (Reichert 2015 ;Nielsen et al 2002 ;Wickham et al 2010 ).…”