Endostatin can inhibit angiogenesis and
tumor growth in mice. A potential limitation of
endostatin as an
antitumor agent in humans is the short serum half-life of the
protein that may decrease effective concentration at the site of
tumor and necessitate frequent dosing. In an effort to improve antitumor activity,
endostatin was fused to an antibody specific for the
tumor-selective HER2
antigen to create an antibody-
endostatin fusion
protein (anti-HER2 IgG3-endostatin). Normal
endostatin rapidly cleared from serum in mice (T(1/2)(2), = 0.6-3.8 hours), whereas anti-HER2 IgG3-endostatin had a prolonged half-life (90% intact; T(1/2)(2), 40.2-44.0 hours).
Antigen-specific targeting of anti-HER2 IgG3-endostatin was evaluated in BALB/c mice implanted with CT26
tumors or CT26
tumors engineered to express the HER2
antigen (CT26-HER2). Radio-iodinated anti-HER2 IgG3-endostatin preferentially localized to CT26-HER2
tumors relative to CT26
tumors. Administration of anti-HER2 IgG3-endostatin to mice showed preferential inhibition of CT26-HER2
tumor growth compared with CT26. Anti-HER2 IgG3-endostatin also markedly inhibited the growth of human
breast cancer SK-BR-3 xenografts in severe combined immunodeficient mice. Anti-HER2 IgG3-endostatin inhibited
tumor growth significantly more effectively than
endostatin, anti-HER2
IgG3 antibody, or the combination of antibody and
endostatin. CT26-HER2
tumors treated with the
endostatin fusion
protein had decreased blood vessel density and branching compared with untreated CT26-HER2 or CT26 treated with the fusion
protein. The enhanced effectiveness of anti-HER2 IgG3-endostatin may be due to a longer half-life, improved serum stability, and selective targeting of
endostatin to
tumors, resulting in decreased angiogenesis. Linking of an antiangiogenic
protein, such as
endostatin, to a targeting antibody represents a promising and versatile approach to antitumor
therapy.