Functional evaluation of novel soluble insulin-like growth factor (IGF)-II–specific ligand traps based on modified domain 11 of the human IGF2 receptor

Prince, Stuart; Foulstone, Emily J.; Zaccheo, Oliver; Williams, Christopher; Hassan, A. Bassim

doi:10.1158/1535-7163.mct-06-0509

Cited by 26 publications

(16 citation statements)

References 74 publications

(59 reference statements)

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“…As such, in the event of high IR-A expression in an IGF-II expressing cancer, alternative strategies of inhibiting IGF signaling may be warranted, such as cotargeting of the IR (or specifically IR-A, if possible), targeting of downstream signaling pathway components (e.g., PI3K), or targeting the ligand itself, the latter strategy already implemented clinically for inhibition of the VEGF pathway with the US Food and Drug Administration-approved drug bevacizumab. The possibility of targeting the IGF-II ligand has recently been suggested as a potential therapeutic strategy for IGF-II dependent osteosarcoma (36) and could be further explored in preclinical and clinical trials of this and other cancer types, given the recent development of inhibitory monoclonal antibodies to IGF-II (60) and a soluble IGF-II trap based on a modified IGF-IIR (61).…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Ulanet

Ludwig²,

Kahn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

221

173

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The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic β cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti–IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti–IGF-1R therapies.

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Section: Discussionmentioning

confidence: 99%

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Ulanet

Ludwig²,

Kahn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

221

173

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“…It binds to the 5′-untranslated region of IGF-II leader-3 mRNA and regulates IGF-II gene expression [18]. IGF-II is one of the principal ligands that bind and activate IGF-I receptor and stimulate its tyrosine phosphorylation [25][26][27]. Tyrosine phosphorylated IGF-I receptor transduces mitogenic signals inside the cell, which may be involved in the tumorigenesis and progression of papillary UC [28,29].…”

Section: Discussionmentioning

confidence: 99%

Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors

Spaulding³

et al. 2008

Human Pathology

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“…One problem appears to be the underestimated effects of IGF1(R) blockade on activation of a central nervous system negative feedback loop, resulting in increased systemic GH driving total IGF1 production from the liver, GH-mediated insulin resistance, and increased insulin supply, resulting in antagonism of the IGF1R inhibitor and systemic metabolic toxicity (20). Similar compensatory feedback responses are also observed with anti-IGF ligand antibodies when administered at therapeutic levels, likely related to the lack of selectivity and subsequent sequestration of free IGF1 (48,49 (14,(50)(51)(52). It is well established that for ligand trap molecules to be functional, a >10-fold higher affinity than that for the signaling receptor appears to be necessary to achieve maximal antagonistic activity (53).…”

Section: R104amentioning

confidence: 94%

“…Because domain 11 AB5 and the combined variant domain 11 AB5-Q1569R P1597H S1602H had affinities exceeding those of endogenous M6P/IGF2R, IGF1R, and IR-A, we evaluated whether these domains could be translated into the basis of improved IGF2 antagonists or ligand traps that function in vivo (14). Human IgG1 Fc fusion domain 11 AB5 and human optimized IgG2 Fc domain 11 AB5-Q1569R P1597H S1602H (domain 11 AB5-RHH hereinafter) were bulk-produced as initial optimized IGF2 antagonists, along with an IgG1 Fc domain 11…”

Section: Development Of Specific and Soluble Igf2 Antagonists Based Omentioning

confidence: 99%

“…This mechanism supports the parental conflict theory of imprinting (6), because loss of M6P/IGF2R function results in IGF2 ligand oversupply and embryonic and placental overgrowth (7-10). Moreover, IGF2:domain 11 binding underpins M6P/IGF2R function as a tumor suppressor, and is the basis for the application of domain 11 as a soluble IGF2 ligand antagonist (11)(12)(13)(14). The relative affinity of IGF2 for the signaling receptors IGF1R and isoform A of insulin receptor (IR-A) is slightly lower (2-20 nM) (15) than the affinity for fulllength M6P/IGF2R (1-2 nM) (16).…”

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confidence: 99%

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Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

Frago

Nicholls

Strickland

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Among the 15 extracellular domains of the mannose 6-phosphate/ insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the k off value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer.growth factor receptor | protein evolution | insulin-like growth factor 2 | binding kinetics | biological therapy T he functional evolution of proteins is largely considered to occur by chance, frequently because of unpredictable and specific events that confer a structure-based change in function sufficient for subsequent selection or "gain of fitness" (1). One such evolutionary biochemical example is the initial acquisition and subsequent gain of affinity between the insulin-like growth factor 2 (IGF2) ligand and a single domain of a nonsignaling mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R) (domain 11). The structural and functional basis of this evolutionary path, which has occurred over 150 million years of mammalian evolution, has been reported previously (2). The questions that we address in the present work are whether the IGF2:domain 11 interaction has reached an optimal state in the context of IGF2 activation of signaling receptors and in the ligand clearance function of M6P/IGF2R, and how far can we extend the binding interaction in terms of structural, biophysical, and functional properties.Functionally, and unlike products of other mammalian imprinted genes, domain 11 is unusual because it specifically evolved to bind to an evolutionary conserved IGF2 ligand with high affinity (3-5). After binding, clearance of extracellular IGF2...

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Functional evaluation of novel soluble insulin-like growth factor (IGF)-II–specific ligand traps based on modified domain 11 of the human IGF2 receptor

Abstract: Ligands transported by the mannose 6-phosphate/insulinlike growth factor (IGF)-II receptor (IGF2R) include IGF-II -and mannose 6-phosphate -modified proteins.

Cited by 26 publications

References 74 publications

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy

Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist

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