KM-1468

Multiple myeloma (MM) is a fatal disease that affects plasma cells. Patients with MM have 1 or more osteolytic lesions in their bone tissues, where insulin‐like growth factors (IGFs; IGF‐I and IGF‐II) are mainly stored. The role of bone‐derived IGFs in the development of MM has not been extensively studied because reliable animal models are lacking. We established an animal model using a human MM cell line, RPMI8226, in nonobese diabetic/severe‐combined immunodeficient (NOD/SCID) mice implanted with human adult bone (HAB) fragments. Treatment with an anti‐human IGF‐neutralizing monoclonal antibody, KM1468, inhibited the IGF‐I‐stimulated phosphorylation of type‐I IGF receptors (IGF‐IR) in RPMI8226 cells and the activation of the downstream PI3‐K/Akt signaling pathway in vitro. KM1468 inhibited IGF‐I‐mediated RPMI8226 cell growth in a dose‐dependent manner. In the NOD/SCID‐HAB model, treatment with KM1468 significantly inhibited the growth of RPMI8226 cells (p < 0.02). These results indicated that the growth of MM cells was predominantly stimulated not by serum‐derived IGFs, but by bone‐derived IGFs. Furthermore, the targeting of bone‐derived IGFs, using a neutralizing antibody, may offer a new therapeutic strategy for MM. © 2005 Wiley‐Liss, Inc.

Environmental stimuli, such as organ-specific growth factors, can influence the metastatic potential of a tumor. The liver is the main source of insulin-like growth factors (IGFs). The importance of IGF signal in hepatic metastasis has been clarified mainly by IGF-I receptor targeting strategies. This study aims to confirm these precedent reports by novel tool, neutralizing antibodies against IGFs and to show that IGFs are promising therapeutic targets for hepatic metastasis in vivo. Hepatic metastasis was induced by intrasplenic injection of human colorectal cancer cell line, HT29. The antimetastatic effects of three antibodies (anti-mouse IGF-I, anti-mouse IGF-II, and anti-human/mouse IGF-II designated KM1468) were tested singly or in combination in the early phase of metastasis. The dose escalation effect of KM1468 and its survival benefit were examined in the early and late phases of metastasis. The mechanism of IGF neutralization was investigated with immunohistochemistry. Dual neutralization of paracrine IGF-I and IGF-II showed modest additive antimetastatic effects than single neutralization of IGF-I or IGF-II. In any phase of metastasis, neutralization led to significant tumor growth inhibition and longer survival. Dose escalation of KM1468 influenced survival only in the late phase of metastasis. Apoptosis increased significantly in the antibody-treated group compared with the control group (P = 0.0025) In conclusion, IGFs are promising therapeutic targets for hepatic metastases of colorectal cancers. However, the IGF dependency is probably variable in the metastatic process.