Depleting soluble ligand (IGF-II) in solid tumor (human breast cancer xenograft) by ligand-specific human monoclonal antibody (2007)

A59 The insulin-like growth factor (IGF) system plays an important role in cancer. Currently several monoclonal antibodies targeting the IGF receptor type I (IGF-IR) are being tested in patients with solid tumors. However, penetration of full-length antibodies into solid tumors is slow and inefficient. We have been hypothesizing that targeting the IGF-IR ligands, IGF-I and IGF-II, by antibodies may not require antibody presence in the tumor interstitial space but could shift the complex equilibrium and quasi-steady states to ligand-antibody complexes in the plasma leading to depletion of the ligand in the tumor. To test this hypothesis we used a fully human monoclonal antibody, IgG1 m610, which binds with high (nM) affinity to IGF-II and inhibits signal transduction mediated by the IGF-II interaction with the IGF-IR (Feng Y., et al., Mol Cancer Therapeutics, 2006, 5:114-120). We chose a mouse xenograft model based on MCF-7 cells because these breast cancer cells produce high levels of IGF-II but do not require this growth factor for their proliferation. IgG1 m610 was administered weekly i.v. at 0, 0.1 or 1 mg/mouse to five week-old nu/nu female mice containing tumors approximately 80 mm3 in size. The concentrations of antibody, IGF-II and IGF-I were measured in plasma and tumor samples before the antibody administration, one hour after the first dose, one hour before the second dose, and one day after the fourth dose corresponding to day 22. The average (per five mice in group) antibody concentration in plasma for the highest dose was 1200 nM one hour after the first dose and 400 nM one hour before the second dose. The corresponding average IgG1 m610 concentration in whole tumor samples was much lower (27 and 8 nM, respectively) than in the plasma indicating poor antibody penetration in tumors as expected; it is likely that the antibody present in the tumor microvasculature is a major component of the measured antibody concentration and the actual antibody concentration in the interstitial fluid is even lower. The IGF-II concentration in tumors was significantly decreased from 24 +/-14 nM (range 11 - 37 nM) to 8 +/-3 nM (range 4-10 nM) after the fourth administration of the antibody at the highest concentration of 1 mg per mouse compared to the control without antibody. The decrease was dependent on the antibody concentration at 0.1 mg per mouse it was on average 1.4-fold. The IGF-II depletion in the interstitial fluid is likely to be much higher - an estimate based on 30% interstitial fluid fraction and uniform IGF-II concentration in the tumor indicates at least 10-fold decrease. The depletion was specific for IGF-II since the IGF-I concentration in the tumor was not affected. These results support concept that full-length antibodies can decrease the concentration of soluble ligands in tumors. Because limited access to interstitial fluid in solid tumors is a major problem for the efficacy of intact antibodies, targeting ligands of growth factors could be an useful strategy for treatment of solid tumors. Targeting of IGF-II could inhibit not only its binding to the IGF-IR but also its binding to the insulin receptor and decrease cell proliferation caused by signals initiated by the IGF-II interaction with both receptors. Thus m610 could be used in combination with anti-IGF-IR antibodies and other anti-cancer drugs for treatment of IGF-II-sensitive solid tumors.