【SABCS2015】聚乙二醇重组人透明质酸酶PH20增强甲磺酸艾日布林对三阴性乳腺癌异种移植物的疗效

[P1-03-09] Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances efficacy of eribulin mesylate (HALAVEN) in triple negative breast cancer xenografts.

Bahn JD, DesJardins C, Condon KB, Fathallah A, Zimmerman S, Maneval DC, Littlefield BA, Thompson CB.

Halozyme Therapeutics, San Diego, CA.

Eisai Inc., Andover, MA.

Hyaluronan (hyaluronic acid, HA), a glycosaminoglycan found in tissue throughout the body, overaccumulates in the tumor microenvironment (TME) of many non-hematologic malignancies, including breast cancer. HA overaccumulation in breast cancer patients correlates with tumor progression and decreased survival (Tammi 2008). Pegylated recombinant human hyaluronidase PH20 (PEGPH20), an investigational therapeutic agent entering Phase 3 clinical development in pancreatic cancer, enzymatically removes HA from the TME. In preclinical animal models, PEGPH20-mediated HA degradation is associated with remodeling of the tumor stroma, reduction of tumor pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy (Thompson 2010, Provenzano 2012, Jacobetz 2013). Accordingly, preclinical studies investigated the combination of PEGPH20 with eribulin mesylate (ERI, HALAVEN), a microtubule dynamics inhibitor with a novel mechanism of action (Towle 2001, Jordan 2005), currently approved for treatment of certain patients with advanced breast cancer. NCr nu/nu mice were inoculated subcutaneously with human triple-negative breast cancer (TNBC) HCC1806 or HCC1806/HAS3 cells; the latter subline was engineered to accumulate high HA levels, confirmed by immunohistochemistry, via overexpression of hyaluronan synthase 3 (HAS3). When tumors reached ～350 mm3, animals were randomly assigned to four treatments groups: vehicle, ERI (0.7 mg/kg, IV, QW), PEGPH20 (37.5 μg/kg, IV, BIW), or ERI plus PEGPH20. In the parental HCC1806 model, addition of PEGPH20 did not significantly change the antitumor effects of ERI. In contrast, combining PEGPH20 with ERI in the HCC1806/HAS3 model increased the antitumor effects of ERI by 27% (94.5% vs. 119.7% TGI, ERI alone vs. ERI+PEGPH20, respectively; p=0.05) and resulted in 6 of 7 complete tumor regressions.

In a complementary study in HCC1806/HAS3 tumors evaluating ERI pharmacokinetics with and without PEGPH20, mice were assigned to three treatments groups: ERI (0.5 mg/kg, IV), simultaneous ERI plus PEGPH20 (37.5 μg/kg, IV); or ERI plus PEGPH20 predosed 24 h prior to ERI. Animals were sacrificed at 0.5, 1, 4, 24, 48, 72 and 96 h post ERI dose, and ERI levels in tumor, muscle, plasma and liver were subsequently analyzed by liquid/liquid extraction and LC-MS/MS chromatography. Simultaneous administration of ERI and PEGPH20 increased ERI maximum tumor concentration (Cmax) slightly and approximately doubled ERI tumor exposure (AUC); whereas the 24 h pretreatment with PEGPH20 approximately doubled ERI Cmax and increased ERI AUC more than two-fold. No significant differences in plasma ERI levels were observed between groups, and no significant differences in ERI levels in liver or muscle tissue were observed between groups. Taken together, these data suggest that PEGPH20-mediated HA removal significantly increases both ERI tumor concentrations and antitumor effectiveness in an HA-high TNBC model. A clinical phase 1b/2 clinical trial is planned to evaluate PEGPH20 plus ERI in first-line HER2-negative metastatic breast cancer.

Wednesday, December 9, 2015 5:00 PM

Poster Session 1: Tumor Cell and Molecular Biology: Microenvironment -- Stromal-Epithelial Interactions (5:00 PM-7:00 PM)

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