Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma

Geoerger, Birgit; Brasme, Jean-François; Daudigeos-Dubus, Estelle; Opolon, Paule; Venot, Corinne; Debussche, Laurent; Vrignaud, Patricia; Vassal, Gilles

doi:10.1016/j.ejca.2010.06.005

Cited by 26 publications

(19 citation statements)

References 37 publications

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“…These findings may prompt reconsideration of cancer therapy targeting IGF-1R and IGF. (30) The anti-IGF-1R antibodies used in clinical trials, known as A12, (35) h7C10, (36) EM164 (37) and CP-751, 871, (38) affect IGF-1R ⁄ Akt pathway, then cell apoptosis and cell proliferation. However, further in vivo experiments are required to support these observations.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of neuroblastoma cell lines in insulin‐like growth factor 1 receptor/Akt pathway‐mediated cell proliferative responses

et al. 2013

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Insulin-like growth factor 1 receptor (IGF-1R) is critical for cancer cell proliferation; however, recent clinical anti-IGF-1R trials did not show clear clinical benefit in cancer therapy. We hypothesized that IGF-1R signaling-mediated proliferative response is heterogeneous in neuroblastoma (NB) cells, and analyzed the cell growth of 31 NB cell lines cultured in three different media, including Hybridoma-SFM medium (with insulin) and RPMI1640 with ⁄ without 10% FBS. Three growth patterns were found. In response to IGF and insulin, cell proliferation and Akt phosphorylation were upregulated in 13 cell lines, and suppressed by MK2206 (Akt inhibitor) and picropodophyllin (IGF-1R inhibitor). Interestingly, 3 of these 13 cell lines showed Akt self-phosphorylation and cell proliferation in RPMI1640; their proliferation was downregulated by anti-IGF-1 or anti-IGF-2 neutralizing antibody, suggesting the existence of an autocrine loop in the IGF-1R ⁄ Akt pathway. Eighteen NB cell lines did not proliferate in RPMI1640, even though Akt phosphorylation was upregulated by IGF and insulin. Based on the heterogeneous response of the IGF-1R ⁄ Akt pathway, the 31 NB cell lines could be classified into group 1 (autocrine IGF-mediated), group 2 (exogenous IGF-mediated) and group 3 (partially exogenous IGF-mediated) NB cell lines. In addition, group 3 NB cell lines were different from group 1 and 2, in terms of serum starvation-induced caspase 3 cleavage and picropodophyllin-induced G2 ⁄ M arrest. These results indicate that the response of the IGF-1R ⁄ Akt pathway is an important determinant of the sensitivity to IGF-1R antagonists in NB. To our knowledge, this is the first report describing heterogeneity in the IGF-1R ⁄ Aktmediated proliferation of NB cells. (Cancer Sci 2013; 104: 1162-1171 N euroblastoma (NB), a malignant tumor that originates from the sympathetic nervous system, is one of the most frequent pediatric solid tumors.(1) NB is characterized by heterogeneous clinical behaviors, tumor invasiveness being different according to age and anatomic stage at diagnosis. The tumor is sometimes completely curable and may even regress spontaneously, especially in younger children.(2) Heterogeneity of the tumors depends on the degree of morphological differentiation and on histopathology. Insulin and insulin-like growth factors (IGF, including IGF-1 and 2) belong to a family of mitogenic growth factors. IGF, insulin, and their receptors are involved in normal growth and differentiation of most tissues. The biological actions of both IGF and insulin can be mediated by the IGF-1 receptor (IGF-1R), a transmembrane heterotetramer, which is involved in mitogenic, anti-apoptotic and oncogenic transforming responses.(4,5) The functional IGF-1R contains two extracellular a-subunits and two intracellular b-subunits that form a heterotetrameric complex. The structural homology of IGF-1R and insulin receptor (IR) allows formation of hybrid receptors (hybrid-R) in which an IGF-1R chain is connected to an IR chain. Ligand interaction with a-...

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Section: Discussionmentioning

confidence: 99%

Heterogeneity of neuroblastoma cell lines in insulin‐like growth factor 1 receptor/Akt pathway‐mediated cell proliferative responses

et al. 2013

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“…EM164 is a humanized anti-IGF-1R antibody that inhibits signaling through IGF-1R. It has been shown to delay growth of human pancreatic cancer and neuroblastoma cells[44, 53]. Ganitumab, an Ab targeted to IGF-1R, was well tolerated in a phase III trial but failed to improve OS in combination with gemcitabine compared to gemcitabine alone in patient s with metastatic pancreatic cancer[54].…”

Section: Signaling Disruptionmentioning

confidence: 99%

Mechanisms of action of therapeutic antibodies for cancer

Redman

Hill

Aldeghaither

et al. 2015

Molecular Immunology

142

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The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

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“…Strategies to target IGF-1R and its ligands, IGF-I and IGF-II, using antibodies are being explored in both pre-clinical models and clinical trials. EM164 is a humanized anti-IGF-1R antibody that has been reported to inhibit signaling through IGF-1R in vitro and delays growth of human pancreatic and neuroblastoma xenografts in vivo [98–99]. Dalotuzumab is another humanized IGF-1R antibody that shows anti-tumor efficacy against breast and lung tumor xenografts [100] and is currently in clinical trials for the treatment of breast (NCT01234857), lung (NCT00654420) and colon cancer (NCT00614393).…”

Section: Targeting Solid Tumorsmentioning

confidence: 99%

Monoclonal antibodies for the treatment of cancer

Shuptrine

Surana

Weiner

2012

Seminars in Cancer Biology

137

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Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer.

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Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma

Cited by 26 publications

References 37 publications

Heterogeneity of neuroblastoma cell lines in insulin‐like growth factor 1 receptor/Akt pathway‐mediated cell proliferative responses

Heterogeneity of neuroblastoma cell lines in insulin‐like growth factor 1 receptor/Akt pathway‐mediated cell proliferative responses

Mechanisms of action of therapeutic antibodies for cancer

Monoclonal antibodies for the treatment of cancer

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