Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti–IGF-IR antibody

Wang, Yan; Hailey, Judith; Williams, Denise; Wang, Yaolin; Lipari, Philip; Malkowski, Michael G.; Wang, Xiaoying; Xie, Lei; Li, Guanghua; Saha, Deba P.; Ling, Wai Lam W.; Cannon-Carlson, Susan; Greenberg, Robert S.; Ramos, Robert; Shields, Robert L.; Presta, Leonard G.; Brams, Peter; Bishop, W. Robert; Pachter, Jonathan A.

doi:10.1158/1535-7163.mct-05-0048

Cited by 141 publications

(93 citation statements)

References 40 publications

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“…Interestingly, we have recently shown that IGF receptor 1 (IGF-1R) is expressed at a significantly higher level in all ER þ tumors (including ER þ /HER2 þ ) compared with ERÀ/HER2 þ tumors (Appl Immunohistochem Mol Morphol; in press). 40 Similar findings were reported by Harris et al 41 If these findings are also supported by additional studies, IGF-1R may be another molecule that could be targeted with available antibodies [42][43][44][45] in these difficult-to-treat ER þ /HER2 þ tumors, despite the presence of two well-known targets.…”

Section: Discussionsupporting

confidence: 70%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

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Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptornegative/HER2 þ tumors is seen in 27-45% of cases. In contrast, estrogen receptor (ER) þ /HER2 þ tumors demonstrate pathologic complete response in B8% of cases and is generally limited to weak-to-moderate ER þ /HER2 þ tumors. It is speculated that addition of trastuzumab to neoadjuvant chemotherapy regimen will increase the pathologic complete response rates in all HER2 þ tumors. A list of HER2 þ patients who received neoadjuvant chemotherapy (with trastuzumab) in the years 2007-2010 was obtained from our hospital database. The 104 HER2 þ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results as follows: ERBB2 (ER-/PR-[H-score r10]/HER2 þ ), Luminal B-HER2 Hybrid (LBHH; weak to moderate ER þ [H-score 11-199]/HER2 þ ), and Luminal A-HER2 Hybrid (LAHH; strong ER þ [H-score Z200]/ HER2 þ ). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and in the lymph nodes. Percentage tumor volume reduction was also calculated based on pretherapy size and detailed evaluation of the resection specimen. In all, 52% (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33%; 10 of 30) and LAHH (8%; 2 of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86%), followed by LBHH (74%) and LAHH (64%) tumors. We conclude that addition of trastuzumab to neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2 þ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be utilized to counsel patients considered for neoadjuvant chemotherapy and the same principle could be applied in the adjuvant setting.

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Section: Discussionsupporting

confidence: 70%

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

et al. 2011

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“…SCH 717454 is a fully human neutralizing IgG1 antibody raised against human IGF-IR using Medarex's HuMab mouse technology (34). SCH 717454 was prepared, stored, and diluted in sodium acetate buffer [20 mmol/L sodium acetate, 150 mmol/L NaCl (pH 5.0-5.5)].…”

Section: Reagentsmentioning

confidence: 99%

“…To minimize the potential for immunologic liabilities of non-human antibodies, several fully human monoclonal antibodies against IGF-1R several fully human monoclonal antibodies against IGF-IR have recently been generated (32)(33)(34)(35). These antibodies exhibit potent antitumor effects in breast, colon, prostate, ovarian, and pancreatic cancers in vitro and in vivo and offer great potential for success as safe and effective human anticancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

“…These antibodies exhibit potent antitumor effects in breast, colon, prostate, ovarian, and pancreatic cancers in vitro and in vivo and offer great potential for success as safe and effective human anticancer therapeutics. We and others have previously described SCH 717454 (19D12, robatumumab), a fully human neutralizing anti-IGF-IR antibody that potently inhibits ligand binding and signaling (34,36,37). SCH 717454 inhibits the growth of various mouse xenograft tumor models.…”

Section: Introductionmentioning

confidence: 99%

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A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Wang¹,

Lipari²,

Wang³

et al. 2010

Molecular Cancer Therapeutics

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The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in the growth, survival, and metastasis of a broad range of malignancies including pediatric tumors. Blocking the IGF-IR action is a potential cancer treatment. A fully human neutralizing monoclonal antibody, SCH 717454 (19D12, robatumumab), specific to IGF-IR, has shown potent antitumor effects in ovarian cancer in vitro and in vivo. In this study, SCH 717454 was evaluated in several pediatric solid tumors including neuroblastoma, osteosarcoma, and rhabdomyosarcoma. SCH 717454 is shown here to downregulate IGF-IR as well as inhibit IGF-IR and insulin receptor substrate-1 phosphorylation in pediatric tumor cells. IGF-IR and insulin receptor substrate-1 phosphorylation in the tumor cells. In vivo, SCH 717454 exhibits activity as a single agent and significantly inhibited growth of neuroblastoma, osteosarcoma, and rhabdomyosarcoma tumor xenografts. Combination of SCH 717454 with cisplatin or cyclophosphamide enhanced both the degree and the duration of the in vivo antitumor activity compared with single-agent treatments. Furthermore, SCH 717454 treatment markedly reduced Ki-67 expression and blood vessel formation in tumor xenografts, showing that the in vivo activity is derived from its inhibition of tumor cell proliferation and angiogenesis activity. Mol Cancer Ther; 9(2); 410-8. ©2010 AACR.

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“…Antibodies against the binding domain of IGF-1R block binding of the ligand and subsequent activation of the receptor [31][32][33][34][35][36][37][38]. Binding of these antibodies can trigger receptor internalization and degradation with reduction in the receptor number on the cell surface.…”

Section: Igf-1r Antibodiesmentioning

confidence: 99%

Role of insulin-like growth factor-1R system in colorectal carcinogenesis

Donovan

Kummar

2008

Critical Reviews in Oncology/Hematology

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The insulin-like growth factor (IGF) system is comprised of receptors, ligands (IGF-I and IGF-II), and a family of binding proteins (IGFBPs). It plays an important role in growth and development and in the maintenance of normal homeostasis. We present a review of the current laboratory and epidemiologic evidence that suggests an important role of the IGF system in colorectal carcinogenesis. Due to the complexity of this system, we have focused the review on the role of the IGF-1 receptor and its ligands in colorectal carcinogenesis and the strategies to block this pathway as a potential anti-cancer therapy.

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Inhibition of insulin-like growth factor-I receptor (IGF-IR) signaling and tumor cell growth by a fully human neutralizing anti–IGF-IR antibody

Abstract: Insulin-like growth factor

Cited by 141 publications

References 40 publications

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer

A Fully Human Insulin-Like Growth Factor-I Receptor Antibody SCH 717454 (Robatumumab) Has Antitumor Activity as a Single Agent and in Combination with Cytotoxics in Pediatric Tumor Xenografts

Role of insulin-like growth factor-1R system in colorectal carcinogenesis

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