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EntreMed, Inc., Rockville, Maryland 20850 [B. K. L. S., H. L., A. H. F., W. H., J. W. M. R. L., C. A. N.], and Department of Surgery, Children's Hospital, and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 [M. S. O.]
Endogenous murine angiostatin, identified as an internal fragment of plasminogen, blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. A recombinant protein comprising kringles 1–4 of human plasminogen (amino acids 93–470) expressed in Pichia pastoris had physical properties (molecular size, binding to lysine, reactivity with antibody to kringles 1–3) that mimicked native angiostatin. This recombinant Angiostatin protein inhibited the proliferation of bovine capillary endothelial cells in vitro. Systemic administration of recombinant Angiostatin protein at doses of 1.5 mg/kg suppressed the growth of Lewis lung carcinoma-low metastatic phenotype metastases in C57BL/6 mice by greater than 90%; administration of the recombinant protein at doses of 100 mg/kg also suppressed the growth of primary Lewis lung carcinomalow metastatic phenotype tumors. These findings demonstrate unambiguously that the antiangiogenic and antitumor activity of endogenous angiostatin resides within kringles 1–4 of plasminogen.
1 This work was supported by National Cancer Institute, NIH, Grant 1 R43 CA6764101 (to B. K. L. S.). Angiostatin is a trademark of EntreMed, Inc.
2 To whom requests for reprints should be addressed, at EntreMed, Inc., 9610 Medical Center Drive, Rockville, MD 20850.
Received 8/30/96. Accepted 2/ 2/97.
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