Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4

Bumbaca, Daniela; Wong, Anne; Drake, Elizabeth A.; Reyes, Arthur E.; Lin, Benjamin C.; Stéphan, Jean-Philippe; Desnoyers, Luc; Shen, Ben-Quan; Dennis, Mark S.

doi:10.4161/mabs.3.4.15786

Cited by 93 publications

(70 citation statements)

References 37 publications

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“…Freezing, cutting, and fixation of the tissues disrupt cells and expose intracellular epitopes that are not normally accessible in vivo and that may be denatured during processing of the tissue; positive staining of some or many tissues that do not correlate with any known epitope or any in vivo effects are common (68). Consistent with the absence of binding to normal tissues, normal pharmacokinetics was observed (69). TRL345 administered to rats as a single i.v.…”

Section: Discussionmentioning

confidence: 59%

“…An NCBI BLAST search of the epitope on gB only identified 9 proteins with Ͼ75% homology to AD-2, and none had a reported tissue distribution corresponding to the staining pattern seen with the high concentration of TRL345. In a published study of a MAb with off-target reactivity, the pharmacokinetics was substantially abnormal (69), but no such effect was observed for TRL345, consistent with all of the sporadic staining being intracellular.…”

Section: Screening Technologymentioning

confidence: 96%

See 1 more Smart Citation

A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types

Kauvar

Liu

Park

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 59%

Section: Screening Technologymentioning

confidence: 96%

A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types

Kauvar

Liu

Park

et al. 2015

Antimicrob Agents Chemother

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“…Several different mAb have been developed to target components of the FGF-FGFR axis: GP369 (Bai et al, 2010), GAL-FR21 (Zhao et al, 2010), GAL-FR22 (Inokuchi et al, 2015), GAL-F2 , MFGR1877S (Fauvel and Yasri, 2014), hLD1.vb (Bumbaca et al, 2011), FP-1039(Marshall et al, 2011, R3Mab (French et al, 2012), PRO-001 (French et al, 2012), 1A6 (Pai et al, 2008) and LD1 (French et al, 2012). Two main mechanisms of action have been considered; either blocking ligand binding (trap-ligand) or preventing receptor dimerization.…”

Section: Antibodies Against Fgfs and Fgfrs And Fgf-ligand Trapmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

177

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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“…Antibodies raised against FGFR3 have been shown to be efficacious in the KMS11 t(4;14) translocated multiple myeloma model and in the RT112 bladder cancer model (22). Recently, a humanized anti-FGFR4 monoclonal antibody was reported to inhibit tumor growth in the HUH7 HCC xenograft model (56), and antibodies against the FGFR4-ligand FGF19 have shown efficacy in preclinical models of colorectal cancer and HCC (57). Little information is available on the tolerability profile of any of these agents.…”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer

Kilgour²,

Smith³

2012

Clinical Cancer Research

382

363

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The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular, and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been observed in numerous tumor settings, whereas the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of preclinical data shows that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target. In the past, development of therapeutic approaches to target this axis has been hampered by our inability to develop FGFR-selective agents. With the advent of a number of new modalities for selectively inhibiting FGF/FGFR signaling, we are now in a unique position to test and validate clinically the many hypotheses that have been generated preclinically.

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Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4

Cited by 93 publications

References 37 publications

A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types

A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer

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