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Introduction Hyaluronan (HA) is a naturally occurring glycosaminoglycan that can accumulate in the tumour microenvironment (TME). In pancreatic and other cancers, high levels of HA are associated with poor clinical outcome. In mouse models, high levels of HA in the TME can increase interstitial fluid pressure and compress tumour vasculature, thereby impairing delivery of anti-cancer therapeutics. Here, a novel, first-in-class biologic that enzymatically degrades HA, PEGPH20, increased tumour vascular volume (VV) and improved anti-tumour efficacy when combined with chemotherapy or checkpoint inhibitor antibodies in multiple HA-accumulating tumour models. Material and methods Various human and mouse cancer cell lines were transduced with hyaluronan synthase 3 (HAS3) to increase HA production, and implanted in the mammary fat pat (4 T1/HAS3) or adjacent to the tibial periosteum (all other cell lines). Tumour VV was measured by high resolution ultrasound coupled with micro-bubbles (A549/HAS3 and WT-CLS1/HAS3), or IHC (CT26/HAS3), following PEGPH20 treatment (0.0375 mg/kg or 1 mg/kg, IV, 2qw). For BxPC3/HAS3 studies, mice were dosed with vehicle or PEGPH20 (4.5 mg/kg, IV, 2qw)±nab paclitaxel (NAB, 10 mg/kg, IV, 2qw)±gemcitabine (GEM, 180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For AsPC1/HAS3 studies, mice were dosed with vehicle or PEGPH20 (0.0375 mg/kg, IV, 2qw)±NAB (10 mg/kg, IV, qw)±GEM (180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For checkpoint inhibitor studies (CT26/HAS3, 4 T1/HAS3, Pan02/HAS3), mice were dosed with PEGPH20 (0.0375 mg/kg, IV) 24 hour prior to anti-CTLA4 (clone 9D9, 4 mg/kg, IP) or anti-PD-L1 (clone 10F.9G2, 5 mg/kg, IP). Results and discussions PEGPH20 administration resulted in degradation of HA in all tumour models tested, and resulted in increased VV in the 3 models tested. PEGPH20 +GEM + NAB led to enhanced tumour growth inhibition (TGI) compared to GEM+NAB in the BxPC3/HAS3 (104% v 70%, respectively, p Conclusion These studies demonstrate that the use of PEGPH20 to enzymatically remodel the TME in HA-high tumours may represent a novel approach for enhancing the efficacy of cancer therapeutics. A Phase 3 study of GEM and NAB ±PEGPH20 in patients with prospectively selected HA-high PDA is ongoing (NCT02715804).

Introduction Hyaluronan (HA), a primary component of the extracellular matrix, can accumulate in a variety of solid malignancies, where histological analyses of patient tumour tissues demonstrated that HA levels may correlate with patient outcomes. HA accumulation in the TME may be associated with poor prognosis. Preclinical studies demonstrated elevated TME HA levels increased tumour interstitial pressure, reduced tumour blood flow, and resulted in poor penetration of anticancer agents and immune cells. A PEGylated recombinant human hyaluronidase, pegvorhyaluronidase alfa (PEGPH20), depolymerizes HA, increases tumour vascular perfusion, and may increase access and anti-tumour efficacy of cytotoxic and immunotherapies. Material and methods Pegvorhyaluronidase alfa is being evaluated in clinical studies for pancreatic, breast, lung, cholangiocarcinoma, and gastric cancers. To broaden the spectrum of possible tumour types that may benefit from pegvyorhyaluronidase alfa, we assessed the prevalence and accumulation of HA in 3633 human histological samples in 22 solid tumour types. HA levels were measured using tissue microarrays (TMAs) stained with a proprietary HA probe, HTI–601, a recombinant immunoadhesin containing a modified HA–specific link domain from TNF-Stimulated Gene 6 protein (TSG–6) and the Fc portion of human IgG1. The resulting HA probe was biotinylated for use in an affinity-based histochemistry method. HA staining was evaluated with research-grade histological image analysis software. HA levels associated with distinct tumour compartments (stroma or tumour cells) were assessed. HA accumulation associated with immune infiltrates present in the TMA cores was also evaluated. Results and discussions Distribution of HA accumulation across compartments fell into 4 main arrangements: - For desmoplastic tumour indications (pancreatic ductal adenocarcinoma, cholangiocarcinoma), the stroma was associated with high percentage of surface area stained with HTI-601 relative to the tumour cells; - Comparable distribution of HA staining in both tumour cells and stroma (gall bladder and glioblastoma); - Sub-clusters of HA staining within a specific tumour type (NSCLC non-squamous); - Distribution bias towards increased or decreased HA intensity staining (head and neck excluding nasopharyngeal cavities and renal cell carcinoma, respectively). Conclusion Understanding HA prevalence and accumulation in solid tumours may potentially identify malignancies that may benefit from pegvorhyaluronidase alfa therapy targeting HA.

senting 54 different chromosome regions, were suggestively associated with knee OA at a threshold of P < 10 -4 . We then tested these SNPs for association with knee OA in cases and controls from the JoCo Study. Of the 87 SNPs available for replication in JoCo, none were significantly associated with knee OA at a nominal P < 0.01. At our tested levels of significance (i.e., P < 10