Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1

Tolcher, Anthony W.; Mita, Monica; Meropol, Neal J.; Mehren, Margaret von; Patnaik, Amita; Padavic, Kristin; Hill, M.; Mays, Theresa A.; McCoy, T. H.; Fox, Norma Lynn; Halpern, Wendy; Corey, A.; Cohen, Roger B.

doi:10.1200/jco.2006.08.8898

Cited by 283 publications

(177 citation statements)

References 11 publications

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“…Some of them are now under various phases of clinical trials (1)(2)(3)10). The advantages of agonistic mAbs compared with TRAIL include specificity of binding to their target receptor without cross-reactivity with the DcRs, much longer serum half-life, and the crystallizable fragment (Fc)-mediated effector functions exploiting human immune system, such as antibody-dependent cellular cytotoxicity, particularly for IgG1 isotype (1,2).…”

Section: Introductionmentioning

confidence: 99%

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A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

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The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we report a novel agonistic mAb, AY4, raised against human DR4 in mice. ELISA analysis revealed that AY4 specifically bound to DR4 without competition with TRAIL for the binding. Despite distinct binding regions of AY4 on DR4 from those of TRAIL, AY4 as a single agent induced caspase-dependent apoptotic cell death of several tumor types through the extrinsic and/or intrinsic pathways without substantial cytotoxicity to normal human hepatocytes. Further, the AY4-sensitive cells followed the same cell death characteristics classified as type I and type II cells by the response to TRAIL, suggesting that the cell death profiles in responses to DR4 and/or DR5 stimulation are determined by the downstream signaling of the receptor rather than the kind of receptor. Noticeably, AY4 efficiently induced cell death of Jurkat cells, which have been reported to be resistant to other anti-DR4 agonistic mAbs, most likely due to the unique epitope property of AY4. In vivo administration of AY4 significantly inhibited tumor growth of human non-small cell lung carcinoma preestablished in athymic nude mice. Conclusively, our results provide further insight into the DR4-mediated cell death signaling and potential use of AY4 mAb as an anticancer therapeutic agent, particularly for

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Section: Introductionmentioning

confidence: 99%

“…In addition to the cognate ligand of recombinant TRAIL, several agonistic monoclonal antibodies (mAb) have been developed by targeting DR4 (7)(8)(9)(10) or DR5 (11)(12)(13)(14)(15)(16), which also induce cell death in various types of tumors in vitro and in vivo. Some of them are now under various phases of clinical trials (1)(2)(3)10).…”

Section: Introductionmentioning

confidence: 99%

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

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“…This clinical failure has been subsequently attributed to the low in vivo bioactivity of the TRAIL molecules administered, and their rather short terminal plasma half-life (»1 hour). 4,6 Consequently, alternative therapeutic strategies targeting TRAIL death receptors have been developed, such as agonistic monoclonal antibodies directed against either DR4, e.g., mapatumumab, 8,9 or DR5, e.g., conatumumab 10 and lexatumumab. 11 However, Phase 1 and 2 clinical studies revealed ambiguous results (for review see refs.…”

Section: Introductionmentioning

confidence: 99%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

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Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumorassociated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N-and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the Nterminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics.

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“…Furthermore, no immunogenicity against mapatumumab or lexatumumab has been observed. Clinical responses ranging from stable disease, partial responses and even a complete response have been reported after administering either untagged versions of recombinant human TRAIL or antibodies targeting death receptors as monotherapy (Plummer et al, 2007;Tolcher et al, 2007;Greco et al, 2008;Hotte et al, 2008;Leong et al, 2009;Mom et al, 2009;Trarbach et al, 2010;Wakelee et al, 2010). Taken together, safety results and clinical responses encourage further diseasedirected assays of these agents.…”

Section: Novel Paradigms For Cancer Therapy V Pavet Et Almentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Phase I Pharmacokinetic and Biologic Correlative Study of Mapatumumab, a Fully Human Monoclonal Antibody With Agonist Activity to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor-1

Cited by 283 publications

References 11 publications

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Towards novel paradigms for cancer therapy

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