Human
pancreatic ribonuclease (
RNase 1) is a small secretory
protein that catalyzes the cleavage of
RNA. This highly cationic
enzyme can enter human cells spontaneously but is removed rapidly from circulation by glomerular filtration. Here, this shortcoming is addressed by attaching a poly(
ethylene glycol) (PEG) moiety to
RNase 1. The pendant has no effect on ribonucleolytic activity but does increase persistence in circulation. The
RNase 1-PEG conjugates inhibit the growth of
tumors in a xenograft mouse model of human
lung cancer. Both retention in circulation and
tumor growth inhibition correlate with the size of the pendant PEG. A weekly dose of the 60-kDa conjugate at 1 µmol/kg inhibited nearly all
tumor growth without affecting
body weight. Its molecular efficacy is ∼5000-fold greater than that of
erlotinib, which is a small molecule in clinical use for the treatment of
lung cancer. These data demonstrate that the addition of a PEG moiety can enhance the in vivo efficacy of human
proteins that act within cells and highlight a simple means of converting an endogenous human
enzyme into a
cytotoxin with potential clinical utility.