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Many tumors are associated with elevated levels of hyaluronan (HA). Through interaction with other extracellular matrix molecules, HA perturbs the delivery of cytostatic agents. Bovine forms of hyaluronidase, an HA degrading enzyme, have shown promise clinically as a chemosensitizing agent in a number of malignancies, but suffered immunologic and pharmacokinetic limitations. We therefore engineered a recombinant soluble form of human hyaluronidase (rHuPH20). The highly purified rHuPH20 enzyme lacked any gross or histologic toxicity across a very broad therapeutic range, and failed to elicit neutralizing antibodies in non human primates. rHuPH20 enhanced the dispersion of molecules up to 200nm in diameter in a dose dependent fashion, and increased hydraulic conductivity over 10 fold. These effects were fully reversible within 24 hours post injection. The enzyme itself was also systemically bioavailable, facilitating the dispersion of indicator dyes injected at distal sites without altering vascular permeability. Application of rHuPH20 to tumor cells in vitro effectively removed pericellular hyaluronan, which rapidly regenerated upon its removal from the culture media. Application of rHuPH20 to human xenograft models resulted in a significant reduction in tumor interstitial fluid pressure within 1 hour of administration. As increased interstitial fluid pressure is a key factor limiting bulk fluid flow in solid tumors, we conclude that recombinant human PH20 warrants testing as an adjunct to increase the therapeutic index of cytostatic regimens.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]