Cancer Immunology, Immunotherapy

, Volume 56, Issue 3, pp 343–357 | Cite as

Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis

  • Kai-Da Wu
  • Li Zhou
  • Douglas Burtrum
  • Dale L. Ludwig
  • Malcolm A. S. Moore
Original Article

Abstract

Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum -induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.

Keywords

Multiple myeloma Receptor tyrosine kinase IGF-IR Human antibody Anti-angiogenesis Targeted therapy 

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Kai-Da Wu
    • 1
  • Li Zhou
    • 1
  • Douglas Burtrum
    • 2
  • Dale L. Ludwig
    • 2
  • Malcolm A. S. Moore
    • 1
  1. 1.James Ewing Laboratory of Developmental Hematopoiesis, Cell Biology ProgramMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.ImClone Systems IncorporatedNew YorkUSA

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