Human Combinatorial Fab Library Yielding Specific and Functional Antibodies against the Human Fibroblast Growth Factor Receptor 3

Rauchenberger, Robert; Borges, Eric; Thomassen-Wolf, Elisabeth; Rom, Eran; Adar, R; Yaniv, Yael; Malka, Michael; Chumakov, Irina; Kotzer, Sarit; Resnitzky, Dalia; Knappik, Achim; Reiffert, Silke U.; Prassler, Josef; Jury, Karin M.; Waldherr, Dirk; Bauer, Susanne; Kretzschmar, Titus; Yayon, Avner; Rothe, Christine

doi:10.1074/jbc.m303164200

Cited by 112 publications

(78 citation statements)

References 82 publications

(87 reference statements)

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“…HuCAL-Fab1, a fully synthetic human combinatorial antibody library 22,23 was used for in vitro selection of antibodies against rat TIMP-1 (data not shown, B. B., unpublished observations, 2001).…”

Section: Resultsmentioning

confidence: 99%

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

et al. 2004

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F ibrosis is associated with many liver diseases, including hepatitis C virus infection, iron deposition, alcohol consumption, and nonalcoholic fatty liver disease. Hepatic fibrosis results from a net increased synthesis and decreased degradation of extracellular matrix (ECM) proteins. Type I collagen is the most prevalent ECM protein deposited, 1 with activated hepatic stellate cells (HSCs) serving as the primary source. Following a fibrogenic stimulus, HSCs activate from their normal quiescent state, whereby they increase synthesis of procollagen type I messenger RNA (mRNA) and protein, 1,2 and increase cellular proliferation, migration, and contractility. 3,4 Excess ECM accumulation results in scarring within the tissue. Our understanding of ECM degradation during hepatic fibrosis is still very limited. ECM degradation is mediated by matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes grouped into collagenases, gelatinases, stromelysins, and membrane-type MMPs, 5 based upon their substrates. Interstitial collagenases (MMP-1 and MMP-13 in humans,

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Section: Resultsmentioning

confidence: 99%

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

et al. 2004

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“…FGFR3 is a candidate target to explain the effect of 17-AAG on synovial sarcoma. This protein not only has a documented role in promoting mesenchymal growth, but expression profiling studies from ourselves (6) and others (9) have highlighted expression of FGFR3 in synovial sarcoma, and furthermore, recent studies have shown antiproliferative activity of FGFR inhibitors in synovial sarcoma (16,22). Our data shows FGFR3 degradation is induced by 17-AAG, although we were unable to show growth inhibition by small molecule or antibody inhibitors of FGFR3 in our assays, which differed from the cited studies in that we did not use exogenous FGF ligand supplementation.…”

Section: Discussionmentioning

confidence: 99%

Hsp90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Prevents Synovial Sarcoma Proliferation via Apoptosis in In vitro Models

Terry

Lubieniecka

Kwan

et al. 2005

Clinical Cancer Research

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Synovial sarcoma is a soft tissue malignancy with a poor prognosis; many patients will die from this disease within 10 years of diagnosis, despite treatment. Gene expression profiling and immunohistochemistry studies have identified oncogenes that are highly expressed in synovial sarcoma. Included in this group are receptor tyrosine kinases such as epidermal growth factor receptor, insulin-like growth factor receptor 1, fibroblast growth factor receptor 3, KIT, and HER2. Inhibitors of these growth-promoting receptors are likely to inhibit proliferation of synovial sarcoma; however, the effect of receptor tyrosine kinase inhibitors on synovial sarcoma is largely unknown. We assessed the ability of the following receptor tyrosine kinase inhibitors to halt proliferation and induce apoptosis in synovial sarcoma monolayer and three dimensional spheroid in vitro models: gefitinib (Iressa), NVP-AEW541, imatinib mesylate (Gleevec), SU5402, trastuzumab (Herceptin), and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Gefitinib, NVP-AEW541, and imatinib inhibited proliferation only at relatively high concentrations, which are not clinically applicable. 17-AAG, which destabilizes multiple receptor tyrosine kinases and other oncoproteins through heat shock protein 90 inhibition, prevented proliferation and induced apoptosis in synovial sarcoma monolayer models at concentrations achievable in human serum. 17-AAG treatment was also associated with receptor tyrosine kinase degradation and induction of apoptosis in synovial sarcoma spheroid models. 17-AAG was more effective than doxorubicin, particularly in the spheroid models. Here we provide in vitro evidence that 17-AAG, a clinically applicable drug with known pharmacology and limited toxicity, inhibits synovial sarcoma proliferation by inducing apoptosis, and thus has potential as a systemic therapy for this disease.Synovial sarcoma accounts for f7% to 10% of soft tissue malignancies and is associated with significant morbidity and mortality (1). Approximately 50% of patients will die from metastatic disease within 10 years of diagnosis despite treatment; the efficacy of conventional chemotherapeutics is controversial, although a recent report has suggested that combination doxorubicin/ifosfamide therapy offers a modest survival advantage in advanced cases (2,3).A translocation between SYT on chromosome 18 and SSX1 or SSX2 on chromosome X is characteristic of synovial sarcoma and is the only apparent cytogenetic abnormality in one third of cases (4). The biological roles of SYT and SSX are poorly understood; studies suggest that SYT functions as a transcriptional activator and SSX as a transcriptional repressor (4), although neither binds DNA directly. This implies that the SYT-SSX fusion protein combines these opposing activities and contributes to the pathogenesis of synovial sarcoma by dysregulating transcriptional patterns (4, 5). Expression profiling studies have identified a number of genes that are highly expressed in synovial sarcoma, including known oncog...

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“…36) that bind human IGF-I with low nanomolar affinity, in three panning cycles as previously described (37) and subsequently subjected to in vitro affinity maturation (38). IGF-IR antibodies used were aIR-3 (Calbiochem, No.…”

Section: Reagents and Cell Linesmentioning

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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Human Combinatorial Fab Library Yielding Specific and Functional Antibodies against the Human Fibroblast Growth Factor Receptor 3

Cited by 112 publications

References 82 publications

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats

Hsp90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Prevents Synovial Sarcoma Proliferation via Apoptosis in In vitro Models

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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