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Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities.

ABSTRACT: Poor pharmacokinetics and resistance within some tumor cell lines have been the major obstacles during the preclinical or clinical application of TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand). The half-life of TRAIL114-281 (114 to 281 amino acids) was revealed to be no more than 30?minutes across species. Therefore maleimido activated PEG (polyethylene glycol) and MMAE (Monomethyl Auristatin E) were applied to site-specifically conjugate with the mutated cysteines from different monomers of TRAIL successively, taking advantage of steric effects involved within TRAIL mutant conjugations. As a result, TRAIL trimer was hetero-modified for different purposes. And the resulting PEG-TRAIL-vcMMAE conjugate exhibited dramatically improved half-life (11.54?h), favourable in vivo targeting capability and antitumor activities while no sign of toxicity in xenograft models, suggesting it's a viable therapeutic and drug delivery strategy.

SUBMITTER: Pan LQ

PROVIDER: S-EPMC4597189 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities.

Pan Li-Qiang LQ Zhao Wen-Bin WB Lai Jun J Ding Ding D Wei Xiao-Yue XY Li Yang-Yang YY Liu Wen-Hui WH Yang Xiao-Yue XY Xu Ying-Chun YC Chen Shu-Qing SQ

Scientific reports 20151008

Poor pharmacokinetics and resistance within some tumor cell lines have been the major obstacles during the preclinical or clinical application of TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand). The half-life of TRAIL114-281 (114 to 281 amino acids) was revealed to be no more than 30 minutes across species. Therefore maleimido activated PEG (polyethylene glycol) and MMAE (Monomethyl Auristatin E) were applied to site-specifically conjugate with the mutated cysteines from di ...[more]

PMID: 26445897

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Project description:Simple Summary The prognosis for advanced Extramammary Paget’s disease (EMPD) is almost always poor. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in cases with the ERBB2-mutation or ERBB2-overexpression. Abstract Extramammary Paget’s disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody–drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients’ clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.

Dataset Information

Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities.

Publications

Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities.

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