Cytotoxic antibody fragments for eliminating undifferentiated human embryonic stem cells

Lim, Denis Y.X.; Ng, Yi-Han; Lee, Jeremy; Mueller, Monika; Choo, Andre; Wong, Voon‐Kean

doi:10.1016/j.jbiotec.2011.03.017

Cited by 24 publications

(20 citation statements)

References 24 publications

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“…A monoclonal antibody against this protein demonstrated cytoxicity against undifferentiated cells, but did not interfere with the progress of differentiating cells [36-38]. Moreover, since natural antibodies with their high molecular weights (IgG, 150 kDa; IgM, 750 kDa) do not penetrate well into embryoid bodies and tissues, single chain variable fragments were engineered with a much smaller molecular weight (20 kDa) and a thus much smaller hydrodynamic cross-section.…”

Section: Review Of Safeguarding Strategiesmentioning

confidence: 99%

“…Moreover, since natural antibodies with their high molecular weights (IgG, 150 kDa; IgM, 750 kDa) do not penetrate well into embryoid bodies and tissues, single chain variable fragments were engineered with a much smaller molecular weight (20 kDa) and a thus much smaller hydrodynamic cross-section. This resulted in much better penetration and much higher efficacy in elimination of potentially tumorigenic stem cells [38]. …”

Section: Review Of Safeguarding Strategiesmentioning

confidence: 99%

“…PluriSIn#1 inhibits stearoyl-CoA desaturase-1, an enzyme involved in metabolism of monounsaturated fatty acid. This leads to apoptosis of the treated cells [38]. …”

Section: Review Of Safeguarding Strategiesmentioning

confidence: 99%

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‘Above all, do no harm’: safeguarding pluripotent stem cell therapy against iatrogenic tumorigenesis

Malecki

2014

Stem Cell Res Ther

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Human pluripotent stem cells are the foundations of regenerative medicine. However, the worst possible complication of using pluripotent stem cells in therapy could be iatrogenic cancerogenesis. Nevertheless, despite the rapid progress in the development of new techniques for induction of pluripotency and for directed differentiation, risks of cancerogenic transformation of therapeutically implanted pluripotent stem cells still persist. 'Above all, do no harm', as quoted from the Hippocratic Oath, is our ultimate creed. Therefore, the primary goal in designing any therapeutic regimes involving stem cells should be the elimination of any possibilities of their neoplasmic transformation. I review here the basic strategies that have been designed to attain this goal: sorting out undifferentiated, pluripotent stem cells with antibodies targeting surface-displayed biomarkers; sorting in differentiating cells, which express recombinant proteins as reporters; killing undifferentiated stem cells with toxic antibodies or antibody-guided toxins; eliminating undifferentiated stem cells with cytotoxic drugs; making potentially tumorigenic stem cells sensitive to pro-drugs by transformation with suicide-inducing genes; eradication of differentiation-refractive stem cells by self-triggered transgenic expression of human recombinant DNases. Every pluripotent undifferentiated stem cell poses a risk of neoplasmic transformation. Therefore, the aforementioned or other novel strategies that would safeguard against iatrogenic transformation of these stem cells should be considered for incorporation into every stem cell therapy trial.

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Section: Review Of Safeguarding Strategiesmentioning

confidence: 99%

Section: Review Of Safeguarding Strategiesmentioning

confidence: 99%

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‘Above all, do no harm’: safeguarding pluripotent stem cell therapy against iatrogenic tumorigenesis

Malecki

2014

Stem Cell Res Ther

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“…Anti-claudin-6 antibodies modified with toxins were effective in killing the targeted stem cells. So were the other antibodies followed by toxins [122–123]. …”

Section: Safeguarding Stem Cell Therapy Against Iatrogenic Cancerogenmentioning

confidence: 99%

Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

Mavroudi¹,

Porpodis²,

Kioumis³

et al. 2014

J Cancer Res Ther

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Introduction Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The statistics speak for themselves with the grim reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem cells’ guided gene therapy. Review of therapeutic strategies in preclinical and clinical trials Stem cells have the unique potential for self renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells only. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we discuss various strategies to safeguard stem cell guided gene therapy against iatrogenic cancerogenesis. Perspectives Defining cancer biomarkers to facilitate early diagnosis, elucidating cancer genomics and proteomics with modern tools of next generation sequencing, and analyzing patients’ gene expression profiles provide essential data to elucidate molecular dynamics of cancer and to consider them for crafting pharmacogenomics-based personalized therapies. Streamlining of these data into genetic engineering of stem cells facilitates their use as the vectors delivering therapeutic genes into specific cancer cells. In this realm, stem cells guided gene therapy becomes a promising new frontier in personalized and targeted therapy of cancer.

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“…Since crosslinking other PCspecific antibodies bound to hESCs is not cytotoxic, the association of mAb 84 to a unique PC epitope (or potentially other additional unknown epitopes on hESCs) induces cytoskeletal reassembly in advance of PC aggregation and pore formation. Studies with antibody fragments revealed that cytotoxicity requires divalency with sufficient flexibility linking the antigen binding domains (Lim et al, 2011). Since pre-treatment of HES-3 hESC and NCCIT cultures with mAb 84 in vitro prevents teratoma formation in a severe combined immunodeficient (SCID) mouse xenograft model mAb 84 has potential applications in clearing tumour-forming undifferentiated hESCs from cultures of differentiated hESCs intended for cell-based, regenerative therapies (Choo et al, 2008;Tan et al, 2009).…”

Section: Podocalyxin Marks Embryonal Carcinomas and Embryonic Stem Cellsmentioning

confidence: 99%

Podocalyxin in the Diagnosis and Treatment of Cancer

McNagny¹,

Hughes²,

Graves³

et al. 2012

Advances in Cancer Management

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Cytotoxic antibody fragments for eliminating undifferentiated human embryonic stem cells

Cited by 24 publications

References 24 publications

‘Above all, do no harm’: safeguarding pluripotent stem cell therapy against iatrogenic tumorigenesis

‘Above all, do no harm’: safeguarding pluripotent stem cell therapy against iatrogenic tumorigenesis

Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

Podocalyxin in the Diagnosis and Treatment of Cancer

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