Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth

Gao, Jin; Chesebrough, Jon; Cartlidge, Susan A.; Ricketts, Sally‐Ann; Incognito, Leonard; Veldman-Jones, Margaret H.; Blakey, David C.; Tabrizi, Mohammad; Jallal, Bahija; Trail, Pamela A.; Coats, Steven; Bosslet, Klaus; Chang, Yong S.

doi:10.1158/0008-5472.can-10-2274

Cited by 112 publications

(83 citation statements)

References 47 publications

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“…In particular, they provide a compelling rationale for a priori identification of patients with tumors that overexpress IR-A and IGF-II in addition to IGF-IR, which may prove a critical determinant of clinical response to monotherapy or combination regimens in molecularly defined subpopulations. This hypothesis has been supported by preclinical studies (8,37) in which high levels of IR expression and elevated mRNA levels of IR-A compared with IR-B have been found in most of the cancer cell lines tested. Other molecular markers may also predict tumor response to IGF-targeting compounds.…”

Section: Predictive Biomarkersmentioning

confidence: 78%

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

et al. 2012

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Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic effects that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. As a result, compounds targeting the IGF axis have become an area of intense preclinical and clinical research for cancer therapeutics. The IGF axis is intimately involved with the insulin-signaling pathway because of their close homologies. This homology may explain hurdles encountered in the clinical development of IGF-targeted therapies, such as less-than-expected antitumor efficacy that may arise from compensatory increases in the activity of insulin receptor isoform A (IR-A), in response to IGF-I receptor (IGF-IR) inhibition and perturbations in glucose homeostasis, arising from the inhibition of insulin receptor isoform B (IR-B) activity. In this brief review, we compare differentiating factors that characterize the 3 major classes of IGF-targeting compounds: therapeutic antibodies that target IGF-IR, small molecule tyrosine kinase inhibitors that inhibit kinase activities of IGF-IR and IR, and antibodies that target IGF ligands. Cancer Res; 72(1); 3-12. Ó2012 AACR.

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Section: Predictive Biomarkersmentioning

confidence: 78%

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

et al. 2012

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“…These antibodies have the advantage to inhibit IGF signaling through both the IGF1R and the IR-A pathways. This approach is not new (Miyamoto et al 2005, Feng et al 2006 but only very recently has been adequately pursued, with promising inhibitory effects on in vivo growth of IGF1-or IGF2-driven tumors (Gao et al 2011). The recent finding that both IR and IGF1R belong to the family of dependence receptors also holds promise for the possible development of innovative therapies (Boucher et al 2010).…”

Section: R137mentioning

confidence: 99%

Insulin receptor and cancer

Belfiore

Malaguarnera²

2011

Endocrine-Related Cancer

243

223

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The widespread epidemic of obesity and type 2 diabetes has raised concern for the impact of these disorders as risk factors for cancer and has renewed the interest for studies regarding the involvement of hyperinsulinemia and insulin receptor (IR) in cancer progression. Overexpression of IR in cancer cells may explain their increased sensitivity to hyperinsulinemia. Moreover, IR isoform A (IR-A) together with autocrine production of its ligand IGF2 is emerging as an important mechanism of normal and cancer stem cell expansion and is a feature of several malignancies. De novo activation of the IR-A/IGF2 autocrine loop also represents a mechanism of resistance to anticancer therapies. Increasing knowledge of the IR role in cancer has important implications for cancer prevention, which should include control of insulin resistance and hyperinsulinemia in the population and meticulous evaluation of new antidiabetic drugs for their metabolic:mitogenic ratio. We are now aware that several anticancer treatments may induce or worsen insulin resistance that may limit therapy efficacy. Future anticancer therapies need to target the IR-A pathway in order to inhibit the tumor promoting effect of IR without impairing the metabolic effect of insulin.

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“…Two agents, BI 836845 and MEDI-573 (35), with this mode of action have been developed. Here, we describe the pharmacologic activity of BI 836845, a fully human mAb that neutralizes the activities of both IGF-I and IGF-II.…”

Section: Igf-i Signals By Binding To the Igf-i Receptor (Igf-ir) Or Tmentioning

confidence: 99%

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

Friedbichler

Hofmann

Kroez

et al. 2014

Molecular Cancer Therapeutics

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Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity to human IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. Ó2013 AACR.

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Dual IGF-I/II–Neutralizing Antibody MEDI-573 Potently Inhibits IGF Signaling and Tumor Growth

Abstract: Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation.

Cited by 112 publications

References 47 publications

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

Targeting the Insulin-like Growth Factor Axis for the Development of Novel Therapeutics in Oncology

Insulin receptor and cancer

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

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