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Ganitumab is a fully human MAB to the human type 1 IGF receptor (IGF1R). Binding assays showed that ganitumab recognized murine IGF1R with sub-nanomolar affinity (K D=0.22 nM) and inhibited the interaction of murine IGF1R with IGF1 and IGF2. Ganitumab inhibited IGF1-induced activation of IGF1R in murine lungs and CT26 murine colon carcinoma cells and tumors. Addition of ganitumab to 5-fluorouracil resulted in enhanced inhibition of tumor growth in the CT26 model. Pharmacological intervention with ganitumab in naïve nude mice resulted in a number of physiological changes described previously in animals with targeted deletions of Igf1 and Igf1r, including inhibition of weight gain, reduced glucose tolerance and significant increase in serum levels of GH, IGF1 and IGFBP3. Flow cytometric analysis identified GR1/CD11b-positive cells as the highest IGF1R-expressing cells in murine peripheral blood. Administration of ganitumab led to a dose-dependent, reversible decrease in the number of peripheral neutrophils with no effect on erythrocytes or platelets. These findings indicate that acute IGF availability for its receptor plays a critical role in physiological growth, glucose metabolism and neutrophil physiology and support the presence of a pituitary IGF1R-driven negative feedback loop that tightly regulates serum IGF1 levels through Gh signaling.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
St Francis Hospital and Medical Center, Hartford, Connecticut, USA
Yale University School of Medicine, New Haven, Connecticut, USA
Mattel Hospital for Children, Los Angeles California, USA
The Department of Animal Science, Cornell University, Ithaca, New York, USA
The Jackson Laboratory, Bar Harbor, Maine, USA
Maine Center for Osteoporosis Research and Education, St Joseph Hospital, Maine, USA
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The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1–34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P = 0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P<0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P<0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in β-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).
