Targeting the Apoptotic Pathway in Chondrosarcoma Using Recombinant Human Apo2L/TRAIL (Dulanermin), a Dual Proapoptotic Receptor (DR4/DR5) Agonist

Subbiah, Vivek; Brown, Robert E.; Buryanek, Jamie; Trent, Jonathan C.; Ashkenazi, Avi; Herbst, Roy S.; Kurzrock, Razelle

doi:10.1158/1535-7163.mct-12-0358

Cited by 55 publications

(33 citation statements)

References 28 publications

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“…Recombinant human TRAIL/Apo2L, also known as PRO1762 developed by Amgen/Genentech, has been the subject of numerous Phase 1, 1a, 2, and 3 clinical trials over the past decade, with minimal adverse effects reported (45,46). There are many intracellular proteins, such as the inhibitors of apoptosis protein (IAPs) family members, that also confer TRAIL resistance to normal cells (47).…”

Section: Discussionmentioning

confidence: 99%

TRAIL-coated leukocytes that kill cancer cells in the circulation

Mitchell

Wayne

Rana

et al. 2014

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

188

199

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Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. Mounting evidence implicates selectinbased adhesive interactions between cancer cells and the blood vessel wall as facilitating this process, in a manner similar to leukocyte trafficking during inflammation. Here, we describe a unique approach to target and kill colon and prostate cancer cells in the blood that causes circulating leukocytes to present the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) on their surface along with E-selectin adhesion receptor. This approach, demonstrated in vitro with human blood and also in mice, mimics the cytotoxic activity of natural killer cells and increases the surface area available for delivery of the receptor-mediated signal. The resulting "unnatural killer cells" hold promise as an effective means to neutralize circulating tumor cells that enter blood with the potential to form new metastases.drug delivery | nanomedicine

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Section: Discussionmentioning

confidence: 99%

TRAIL-coated leukocytes that kill cancer cells in the circulation

Mitchell

Wayne

Rana

et al. 2014

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

188

199

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“…These clinical studies demonstrated, in line with preclinical results, that the therapeutic concept of apoptosis induction via DR4 and/or DR5 is generally well tolerated. Although antitumor activity was observed for individual patients, the overall response rates were disappointing and could not confirm the promising preclinical results for the different TRAIL-R agonists (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Despite potent antitumor efficacy of all TRAIL-R agonists in xenograft tumor models derived from various human cancer cell lines during preclinical development, translation of the preclinical antitumor efficacy into the clinical setting has not yet been successful.…”

Section: Introductionmentioning

confidence: 97%

APG350 Induces Superior Clustering of TRAIL Receptors and Shows Therapeutic Antitumor Efficacy Independent of Cross-Linking via Fcγ Receptors

Gieffers

Kluge

Merz

et al. 2013

Molecular Cancer Therapeutics

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Cancer cells can be specifically driven into apoptosis by activating Death-receptor-4 (DR4; TRAIL-R1) and/ or Death-receptor-5 (DR5; TRAIL-R2). Albeit showing promising preclinical efficacy, first-generation protein therapeutics addressing this pathway, especially agonistic anti-DR4/DR5-monoclonal antibodies, have not been clinically successful to date. Due to their bivalent binding mode, effective apoptosis induction by agonistic TRAIL-R antibodies is achieved only upon additional events leading to antibody-multimer formation. The binding of these multimers to their target subsequently leads to effective receptor-clustering on cancer cells. The research results presented here report on a new class of TRAIL-receptor agonists overcoming this intrinsic limitation observed for antibodies in general. The main feature of these agonists is a TRAIL-mimic consisting of three TRAIL-protomer subsequences combined in one polypeptide chain, termed the single-chain TRAILreceptor-binding domain (scTRAIL-RBD). In the active compounds, two scTRAIL-RBDs with three receptor binding sites each are brought molecularly in close proximity resulting in a fusion protein with a hexavalent binding mode. In the case of APG350-the prototype of this engineering concept-this is achieved by fusing the Fc-part of a human immunoglobulin G1 (IgG1)-mutein C-terminally to the scTRAIL-RBD polypeptide, thereby creating six receptor binding sites per drug molecule. In vitro, APG350 is a potent inducer of apoptosis on human tumor cell lines and primary tumor cells. In vivo, treatment of mice bearing Colo205-xenograft tumors with APG350 showed a dose-dependent antitumor efficacy. By dedicated muteins, we confirmed that the observed in vivo efficacy of the hexavalent scTRAIL-RBD fusion proteins is-in contrast to agonistic antibodies-independent of FcgR-based cross-linking events.

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“…A leading strategy is to target death receptor 4 (DR4) and/or DR5, which are overexpressed on various tumors. A recombinant soluble version of the cognate ligand, human Apo2L/TRAIL (dulanermin), and several agonistic anti-DR4 or anti-DR5 antibodies have been studied in preclinical models and in patients (10)(11)(12)(13)(14)(15)(16). Despite remarkable preclinical efficacy, only rare clinical responses have been observed.…”

mentioning

confidence: 99%

Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display

Nair¹,

Flores

Gogineni

et al. 2015

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

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TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosisinducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes-synthetic lipid-bilayer nanospheres-similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.cell death | membrane display | caspase | apoptosis | death receptor

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Targeting the Apoptotic Pathway in Chondrosarcoma Using Recombinant Human Apo2L/TRAIL (Dulanermin), a Dual Proapoptotic Receptor (DR4/DR5) Agonist

Cited by 55 publications

References 28 publications

TRAIL-coated leukocytes that kill cancer cells in the circulation

TRAIL-coated leukocytes that kill cancer cells in the circulation

APG350 Induces Superior Clustering of TRAIL Receptors and Shows Therapeutic Antitumor Efficacy Independent of Cross-Linking via Fcγ Receptors

Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display

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