Cancer is a disease showing high mortality, and the object of treatments with anticancer agents generally lies in improvement of the patient's quality of life (“QOL”) and extension of survival time. However, it is difficult to determine the life prolongation effect of a drug in a short period of time, and therefore tumor reduction rate and blood tumor antigen level are often used as surrogate markers of the therapeutic effect of anticancer agents.
Further, since the life prolongation period for determining drug effect in clinical studies of anticancer agents requires a long-term study, tumor reduction rate, which can be evaluated in a relatively short period of time, has also been used as a surrogate marker. However, it has been pointed out that the tumor reduction rate cannot necessarily serve as an index of life prolongation. Accordingly, attempts have been made to use time to disease progression, length of disease free survival period, and/or biological markers etc. as surrogate markers. However, these methods have not yet been validated.
The following have been reported as surrogate markers:
1) Panorex, which is an antibody directed to glycoprotein EpCAM, was first identified as a tumor marker of colon cancer cells and was later found to be an adhesion molecule. Its correlation with survival rate is being examined to evaluate whether it can be used as a surrogate marker for elimination of microcarcinoma cells remaining in bone marrow (Stephan B. et al., Clinical Cancer Research, 1999, 5, 3999–4004) Large-scale phase-III clinical studies are being conducted in parallel.
2) The prostatic specific antigens have been used as a surrogate marker in hormone therapy of prostatic cancer to determine optimum doses (Denis L. & Mahler C. Urology, 1996, 47 (1A Suppl.), 26–32).
3) Matrix metalloprotease inhibitors have been tested as potential surrogate markers for angiogenesis inhibition. For example, a method of using BMS275291 has been examined in a phase I clinical trial as a potential surrogate marker for angiogenesis in wound healing (after a wound has been made in the skin. A method of using the enzymatic activity of a different metallproteinase inhibitor as a surrogate marker for angiogenesis at a tumor site has also been reported (Clin. Cancer Res., 2000, 6(8), 3290–6).
Angiogenesis inhibitors are expected to serve as effective therapeutic agents for diseases other than cancer. For example, such agents are expected to be useful in the treatment of arteriosclerosis, diabetic retinopathy, occlusion of retinal veins, retinopathy of prematurity, age-related macular degeneration, neovascular glaucoma, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, angioma, angiofibroma and so forth. If a surrogate marker of angiogenesis is found, it becomes possible to use that marker to determine, for example, a proper dose of a drug, an effect of a drug and/or a desirable administration protocol for a drug for each of these diseases.
Integrins are cell adhesion molecules expressed on a cell surface and composed of an α-chain and a β-chain. Integrins are involved in adhesion between extracellular matrix membrane proteins and cells, as well as in adhesion between cells. When a cell adhesion molecule binds to integrin, signal systems in the cell are initiated. As a result, not only cell adhesion, but also cell extension, cell growth, apoptosis, differentiation, cytoskeleton orientation, cell migration, tissue formation, cancer invasion and metastasis, wound healing, blood coagulation etc. occur.
Among the integrins, integrin α2β1 is known to act as an adhesion molecule on collagen, laminin and so forth, and also to be involved in the tube formation of vascular endothelial cells during angiogenesis (George E. et al., Exp. Cell. Res., 1996, 224, 39–51). Further, it has also been reported that antibodies directed to integrin α1 and integrin α2 inhibited the angiogenesis induced by VEGF in vivo (Donald R. S. et al., Proc. Natl. Acad. Sci. USA., 1997, 94, 13612–13617).
Integrin αvβ3 specifically exists in endothelial cells undergoing angiogenesis, and it has been reported that the integrin αvβ3 neutralizing antibody (LM609) inhibited the angiogenesis induced by fibroblast growth factor-2 (FGF-2) in an angiogenesis model utilizing chick embryo chorioallantois (Brook, P. C. et al., Science, 1994, 264, 569–571). Further, it has also been reported that integrin αvβ3 is involved in angiogenesis induced by FGF-2 and tumor necrosis factor-α, and that integrin αvβ5 is involved in angiogenesis induced by vascular endothelial growth factor (VEGF) and transforming growth factor-α (Friedlander, M. et al., Science, 1995, 270, 1500–1502). The anti-integrin αvβ3 antibody and the integrin αvβ3 inhibitor are currently in clinical studies.