PO-298 Pegylated recombinant human hyaluronidase PH20 (PEGPH20) increases tumour uptake and efficacy of cetuximab in a human pancreatic cancer xenograft model

Introduction Hyaluronan (HA) accumulation in the ECM of many solid tumours correlates with tumour progression and poor prognosis. In preclinical models, enzymatic degradation of ECM HA with PEGPH20 is associated with remodelling of the tumour stroma, reduction of tumour interstitial fluid pressure, and expansion of tumour blood vessels, resulting in facilitated delivery of anti-cancer agents. Cetuximab (CET), a chimeric monoclonal antibody, targets human EGFR preventing tyrosine kinase-mediated phosphorylation and subsequent signal transduction. Studies were performed to quantitatively assess tumour CET content, plasma PK, and efficacy of CET±PEGPH20 in human xenograft tumour bearing mice. Material and methods Nude mice bearing EGFR-positive peritibial human pancreatic BxPC-3 tumours overexpressing human HA synthase 3 (HAS3) were used to evaluate the effects of PEGPH20 in combination with CET. To evaluate PK, mice were dosed IV with 37.5 µg/kg PEGPH20 and IP with 0.03 mg/kg CET. Plasma samples were collected and analysed for CET concentration by ECL immunoassay. To evaluate tumour uptake, CET was radiolabeled with 89 Zr and administered IV±PEGPH20, and PET scans were acquired over 24 hours. To evaluate anti-tumour efficacy, 37.5 µg/kg PEGPH20 was delivered IV, 0.03 mg/kg CET was administered IP biweekly, and tumour growth was measured over time. Results and discussions Significantly higher 89 Zr uptake into BxPC-3/HAS3 tumours was observed by PET imaging in PEGPH20-treated mice, compared to vehicle alone. PEGPH20 administration immediately prior to 89 Zr-CET resulted in significantly increased tumour maximum standardised uptake value (SUV) compared to CET alone (9.4 vs 6.5 meanSUV max ; p=0.039). Similarly, PEGPH20 administration 24 hour prior to 89 Zr-CET showed increased tumour SUV that was nearly significant compared to CET alone (8.8 vs 6.5 meanSUV max ; p=0.051). PK analysis indicated decreased plasma CET exposure when combined with PEGPH20. Whether PEGPH20 was administered immediately prior to CET or administered 24 hour prior to CET, plasma CET levels at 24 hour after CET dosing were approximately half the concentration of that obtained when CET was administered alone. Administration of PEGPH20 alone inhibited tumour growth by 46% compared to vehicle. The addition of PEGPH20 increased CET tumour growth inhibition (TGI) from 67% to 82% (p Conclusion Tumour imaging and PK studies in nude mice demonstrated increased tumour uptake and reduced systemic exposure of CET, which corresponded with enhanced TGI when CET was combined with PEGPH20.