An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies

Schonfeld, D.L.; Matschiner, Gabriele; Chatwell, Lorenz; Trentmann, Stefan; Gille, Hendrik; Hülsmeyer, Martin; Brown, Najmeeyah; Kaye, Paul M.; Schlehuber, S.; Hohlbaum, Andreas M.; Skerra, Arne

doi:10.1073/pnas.0813399106

Cited by 99 publications

(81 citation statements)

References 32 publications

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“…Blockade of cytotoxic T-lymphocyte associated (CTLA)-4, a negative regulator of T-cell costimulation using either mAb [26] or anticalin therapy [27] has a beneficial effect in experimental VL, and anti-CTLA-4 also showed significant synergy with Sb v [24]. Most recently, a receptor tyrosine kinase inhibitor (sunitinib maleate), used clinically in the treatment of renal cell carcinoma [28,29], was shown to be able to restore lymphoid tissue microarchitecture in an experimental model of VL, and to provide a tenfold dose-sparing effect when used in a pretreatment regimen with Sb v [30].…”

Section: Combined Immunochemotherapymentioning

confidence: 99%

Immunomodulators: use in combined therapy against leishmaniasis

Dalton

Kaye

2010

Expert Review of Anti-infective Therapy

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Section: Combined Immunochemotherapymentioning

confidence: 99%

Immunomodulators: use in combined therapy against leishmaniasis

Dalton

Kaye

2010

Expert Review of Anti-infective Therapy

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“…The lipocalins form a family of structurally conserved human proteins involved in binding and transporting diverse molecules (small molecules and large proteins; 30,31). The b strands that make up the lipocalins and Anticalins are connected by 4 loop regions that can be engineered (randomized) to generate Anticalins with exquisite specificity for molecular targets (31).…”

Section: Introductionmentioning

confidence: 99%

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Olwill

Joffroy

Gille

et al. 2013

Molecular Cancer Therapeutics

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Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients. Mol Cancer Ther; 12(11); 2459-71. Ó2013 AACR.

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“…Although providing CTLA-4 inhibiting antibodies like Ipilimumab along with DNA vaccination is not feasible, other options could be explored. For example, recently characterized genetically engineered lipocalin (LCN2) exhibits a strong cross-species antagonistic activity to CTLA-4 [61]. It is likely that this molecule could be included into DNA vaccine composition to enhance DC-mediated activation of the T cells.…”

Section: Dna Vaccinationmentioning

confidence: 99%