Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models.
Hyaluronan (HA) is a glycosaminoglycan polymer that often accumulates in malignancy. Megadalton complexes of HA with proteoglycans create a hydrated connective tissue matrix, which may play an important role in tumor stroma formation. Through its colloid osmotic effects, HA complexes contribute to tumor interstitial fluid pressure, limiting the effect of therapeutic molecules on malignant cells. The therapeutic potential of enzymatic remodeling of the tumor microenvironment through HA depletion was initially investigated using a recombinant human HA-degrading enzyme, rHuPH20, which removed HA-dependent tumor cell extracellular matrices in vitro. However, rHuPH20 showed a short serum half-life (t(1/2) < 3 minutes), making depletion of tumor HA in vivo impractical. A pegylated variant of rHuPH20, PEGPH20, was therefore evaluated. Pegylation improved serum half-life (t(1/2) = 10.3 hours), making it feasible to probe the effects of sustained HA depletion on tumor physiology. In high-HA prostate PC3 tumors, i.v. administration of PEGPH20 depleted tumor HA, decreased tumor interstitial fluid pressure by 84%, decreased water content by 7%, decompressed tumor vessels, and increased tumor vascular area >3-fold. Following repeat PEGPH20 administration, tumor growth was significantly inhibited (tumor growth inhibition, 70%). Furthermore, PEGPH20 enhanced both docetaxel and liposomal doxorubicin activity in PC3 tumors (P < 0.05) but did not significantly improve the activity of docetaxel in low-HA prostate DU145 tumors. The ability of PEGPH20 to enhance chemotherapy efficacy is likely due to increased drug perfusion combined with other tumor structural changes. These results support enzymatic remodeling of the tumor stroma with PEGPH20 to treat tumors characterized by the accumulation of HA.
Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, CA 92121, USA.
Curtis B
CB
Thompson
H Michael
HM
Shepard
Patrick M
PM
O'Connor
Salam
S
Kadhim
Ping
P
Jiang
Ryan J
RJ
Osgood
Louis H
LH
Bookbinder
Xiaoming
X
Li
Barry J
BJ
Sugarman
Robert J
RJ
Connor
Sinisa
S
Nadjsombati
Gregory I
GI
Frost
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004357:Drug Synergism; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20