Development of an Fn14 agonistic antibody as an anti-tumor agent.

Molecular Discovery, Biogen Idec, 12 Cambridge Center, Cambridge, MA, USA.
mAbs (Impact Factor: 4.73). 07/2011; 3(4):362-75. DOI: 10.4161/mabs.3.4.16090
Source: PubMed

ABSTRACT TWEAK, a TNF family ligand with pleiotropic cellular functions, was originally described as capable of inducing tumor cell death in vitro. TWEAK functions by binding its receptor, Fn14, which is up-regulated on many human solid tumors. Herein, we show that intratumoral administration of TWEAK, delivered either by an adenoviral vector or in an immunoglobulin Fc-fusion form, results in significant inhibition of tumor growth in a breast xenograft model. To exploit the TWEAK-Fn14 pathway as a therapeutic target in oncology, we developed an anti-Fn14 agonistic antibody, BIIB036. Studies described herein show that BIIB036 binds specifically to Fn14 but not other members of the TNF receptor family, induces Fn14 signaling, and promotes tumor cell apoptosis in vitro. In vivo, BIIB036 effectively inhibits growth of tumors in multiple xenograft models, including colon (WiDr), breast (MDA-MB-231), and gastric (NCI-N87) tumors, regardless of tumor cell growth inhibition response observed to BIIB036 in vitro. The anti-tumor activity in these cell lines is not TNF-dependent. Increasing the antigen-binding valency of BIB036 significantly enhances its anti-tumor effect, suggesting the contribution of higher order cross-linking of the Fn14 receptor. Full Fc effector function is required for maximal activity of BIIB036 in vivo, likely due to the cross-linking effect and/or ADCC mediated tumor killing activity. Taken together, the anti-tumor properties of BIIB036 validate Fn14 as a promising target in oncology and demonstrate its potential therapeutic utility in multiple solid tumor indications.

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    ABSTRACT: The cytokine TWEAK and its receptor, Fn14, have emerged as potentially valuable targets for cancer therapy. Granzyme B (GrB)-containing Fn14-targeted constructs were generated containing either the Fn14 ligand TWEAK (GrB-TWEAK) or an anti-Fn14 humanized single-chain antibody (GrB-Fc-IT4) as the targeting moieties. Both constructs showed high affinity and selective cytotoxicity against a panel of Fn14-expressing human tumor cells including triple-negative breast cancer (TNBC) lines. Cellular expression of the GrB inhibitor PI-9 in target cells had no impact on the cytotoxic effect of either construct. Cellular expression of MDR1 showed no cross-resistance to the fusion constructs. GrB-TWEAK and GrB-Fc-IT4 activated intracellular caspase cascades and cytochrome C-related pro-apoptotic pathways consistent with the known intracellular functions of GrB in target cells. Treatment of mice bearing established HT-29 xenografts with GrB-TWEAK showed significant tumor growth inhibition compared to vehicle alone (P < 0.05). Both GrB-TWEAK and GrB-Fc-IT4 displayed significant tumor growth inhibition when administered to mice bearing orthotopic MDA-MB-231 (TNBC) tumor xenografts. TCGA analysis revealed that Fn14 mRNA expression was significantly higher in TNBC and in HER2-positive disease (P<0.0001) compared to hormone receptor-positive breast cancer, and in basal-like 2 tumors (P=0.01) compared to other TNBC molecular subtypes. Immunohistochemistry analysis of a 101 patient TNBC tumor microarray showed that 55/101 (54%) of tumors stained positive for Fn14 suggesting that this may be an excellent potential target for precision therapeutic approaches. Targeting Fn14 using fully-human, GrB-containing fusion constructs may form the basis for a new class of novel, potent and highly effective constructs for targeted therapeutic applications.
    Molecular Cancer Therapeutics 09/2014; 13(11). DOI:10.1158/1535-7163.MCT-14-0346 · 6.11 Impact Factor
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    PLoS ONE 11/2014; 9(11):e104227. DOI:10.1371/journal.pone.0104227 · 3.53 Impact Factor
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    Seminars in Immunology 06/2014; DOI:10.1016/j.smim.2014.02.006 · 6.12 Impact Factor

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