Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy

Liu, X; Wu, Jun; Zhang, S; Li, C; Huang, Qian

doi:10.1038/cgt.2009.30

Cited by 10 publications

(5 citation statements)

References 35 publications

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“…staining by both commercial rabbit anti-P2X 3 antibody and DyLight ® 594-labelled rabbit anti-P2X 3 scFv antibody). Moreover, as the DyLight ® 594-labelled rabbit anti-P2X 3 scFv antibody shared a similar staining pattern with commercial anti-P2X 3 antibody and data published previously [39][40][41], it can be concluded that MH7C effectively binds to both human-and rat-expressed P2X 3 .…”

Section: Discussionsupporting

confidence: 59%

Targeted delivery of a SNARE protease to sensory neurons using a single chain antibody (scFv) against the extracellular domain of P2X3 inhibits the release of a pain mediator

Meng

Wang

et al. 2014

Biochemical Journal

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P2X3 (P2X purinoceptor 3) is predominantly expressed on nociceptive sensory neurons and plays a crucial role in signalling leading to chronic inflammatory pain and some features of neuropathic pain. Thus it represents a potential target for pain therapeutics. BoNT/A (botulinum neurooxin type A) effectively relieves certain types of pain through inhibiting the neuronal release of pain peptides. A recombinant single-chain variable fragment (scFv) antibody designated MH7C was generated against the extracellular domain of P2X3 using phage display. The genes encoding the scFv and activated di-chain form of BoNT/A without the C-terminal-binding subdomain (LC-HN-HCN/A) were ligated and expressed in Escherichia coli cells as a composite fusion protein. The purified protein bound and entered P2X3-containing sensory neurons, cleaved synaptosomal-associated protein of 25 kDa and inhibited the release of a pain peptide. This novel fusion protein designated 'LC-HN-HCN/A-MH7C' has potential clinical applications in the treatment of chronic inflammatory and sympathetically maintained neuropathic pain.

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Section: Discussionsupporting

confidence: 59%

Targeted delivery of a SNARE protease to sensory neurons using a single chain antibody (scFv) against the extracellular domain of P2X3 inhibits the release of a pain mediator

Meng

Wang

et al. 2014

Biochemical Journal

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“…Ad5/3‐BPSA‐ONC EGFR is to the best of our knowledge the first oncolytic virus encoding an immunoRNase or, more generally, immunotoxin. A replication‐deficient Ad vector encoding an active Pseudomonas exotoxin‐based, Her2‐specific immunotoxin has been reported previously . This study did not report whether immunotoxin expression affected vector production, as it was the case for Ad5‐CMV‐ONC EGFR in our study.…”

Section: Discussionmentioning

confidence: 59%

“…Correspondingly, Liu et al . did not observe an increase in vector‐encoded transgene expression after intramuscular and intravenous coinjection with an oncolytic Ad and an only twofold increase after intraperitoneal coinjection. Certainly, inserting the therapeutic gene directly into the oncolytic Ad genome is the superior approach when aiming at increasing expression of the protein drug from amplified virus genomes.…”

Section: Discussionmentioning

confidence: 69%

Genetic delivery of an immunoRNase by an oncolytic adenovirus enhances anticancer activity

Fernández-Ulibarri

Hammer

Arndt

et al. 2014

Intl Journal of Cancer

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Antibody therapy of solid cancers is well established, but suffers from unsatisfactory tumor penetration of large immunoglobulins or from low serum retention of antibody fragments. Oncolytic viruses are in advanced clinical development showing excellent safety, but suboptimal potency due to limited virus spread within tumors. Here, by developing an immunoRNase‐encoding oncolytic adenovirus, we combine viral oncolysis with intratumoral genetic delivery of a small antibody‐fusion protein for targeted bystander killing of tumor cells (viro‐antibody therapy). Specifically, we explore genetic delivery of a small immunoRNase consisting of an EGFR‐binding scFv antibody fragment fused to the RNase Onconase (ONCEGFR) that induces tumor cell death by RNA degradation after cellular internalization. Onconase is a frog RNase that combines lack of immunogenicity and excellent safety in patients with high tumor killing potency due to its resistance to the human cytosolic RNase inhibitor. We show that ONCEGFR expression by oncolytic adenoviruses is feasible with an optimized, replication‐dependent gene expression strategy. Virus‐encoded ONCEGFR induces potent and EGFR‐dependent bystander killing of tumor cells. Importantly, the ONCEGFR‐encoding oncolytic adenovirus showed dramatically increased cytotoxicity specifically to EGFR‐positive tumor cells in vitro and significantly enhanced therapeutic activity in a mouse xenograft tumor model. The latter demonstrates that ONCEGFR is expressed at levels sufficient to trigger tumor cell killing in vivo. The established ONCEGFR‐encoding oncolytic adenovirus represents a novel agent for treatment of EGFR‐positive tumors. This viro‐antibody therapy platform can be further developed for targeted/personalized cancer therapy by exploiting antibody diversity to target further established or emerging tumor markers or combinations thereof.

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“…Another promising strategy is to deliver immunotoxin therapy through gene therapy vectors. Huang et al [ 152 ] evaluated a gene therapy approach designed to express intratumoral therapeutic levels of the e23/PE40 fusion protein to target HER2/neu-expressing tumors. The advantages of gene therapy vectors are that they can mediate continuous and prolonged immunotoxin production and may provide reduced host immune response [ 140,153 ] .…”

Section: From Preclinical Development To Therapeutic Applicationmentioning

confidence: 99%

Design, Development, and Characterization of Recombinant Immunotoxins Targeting HER2/neu

Cao

Rosenblum

2012

Antibody-Drug Conjugates and Immunotoxins

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BackgroundThe human epidermal growth factor receptor 2 (HER2), also known as ErbB2, c-erbB2, or HER2/neu, was initially discovered in 1985 by two independent laboratories [ 1,2 ] . HER2/neu is a 185 kDa (1,255 aa) transmembrane receptor encompassing an intracellular tyrosine kinase domain and an extracellular ligand binding component [3][4][5] . Extensive clinical studies have shown that overexpression of HER2/neu is found in 20-40% of patients with breast, ovarian, endometrial, gastric, bladder, prostate, and lung cancers. Studies clearly demonstrate that HER2/neu overexpression correlates with the prevalence of metastatic spread of many tumors and is generally considered to be a poor prognostic indicator [6][7][8][9] .Since HER2/neu overexpression by tumor cells is quite speci fi c, therapies directed against this receptor have rapidly gained recognition for their selectivity and ef fi cacy in the clinical setting. While targeting of HER2/neu with humanized antibodies such as trastuzumab (Herceptin; Genentech) has proven to be an effective approach for the treatment of HER2/neu-overexpressing breast cancers, there are a signi fi cant number of patients with HER2/neu-positive tumors who do not respond or who acquire resistance to this therapy [10][11][12][13] . Therefore, there is a need for novel therapeutic approaches using HER2/neu not only as a target for interfering with the growth factor signaling component but also for receptor-mediated delivery of cytotoxic agents.Immunotoxins are a novel approach for the development of highly speci fi c, targeted agents and which generally employ a powerful class of protein toxins [ 14,15 ] . These include plant toxins such as ricin [16][17][18][19][20][21][22][23][24][25] , saporin [26][27][28][29] , and gelonin [30][31][32] Diphtheria toxin (DT) [ 33 ] and Pseudomonas exotoxin (PE) [34][35][36][37][38][39][40][41][42][43] , which ADP ribosylate elongation factor 2 (EIF2). Anti-HER2/neu immunotoxins have been created initially by chemically conjugating an antibody to a whole protein toxin or, for more selective activity, using a protein toxin devoid of its natural binding domain [ 19,23, 30,44 ] . Technical advances in antibody engineering now enable us to produce various antibodies or antibody fragments in Escherichia coli , and as a result, HER2/neu-speci fi c antibodies and engineered fragments thereof have been developed to deliver various toxins to HER2/neu-positive tumor cells [45][46][47][48][49][50][51] . Various anti-HER2/neu immunotoxins which have been developed or are currently under evaluation are described in Table 18.1 . Antibody-Drug Conjugates: Promise and ProblemsAntibody-based therapeutics is of growing signi fi cance for cancer therapy. To date, two of the most promising strategies to enhance the antitumor activity of antibodies are antibody-drug conjugates (ADCs) and antibodies (or fragments) chemically conjugated or genetically fused to various toxins (immunotoxins).One successful application of the ADC approach is Trastuzumab-DM1. This is a cov...

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Novel strategies to augment genetically delivered immunotoxin molecular therapy for cancer therapy

Cited by 10 publications

References 35 publications

Targeted delivery of a SNARE protease to sensory neurons using a single chain antibody (scFv) against the extracellular domain of P2X3 inhibits the release of a pain mediator

Targeted delivery of a SNARE protease to sensory neurons using a single chain antibody (scFv) against the extracellular domain of P2X3 inhibits the release of a pain mediator

Genetic delivery of an immunoRNase by an oncolytic adenovirus enhances anticancer activity

Design, Development, and Characterization of Recombinant Immunotoxins Targeting HER2/neu

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