Immune-tolerant elastin-like polypeptides (iTEPs) and their application as CTL vaccine carriers

Cho, Scott; Dong, Shuyun; Parent, Kristin N.; Chen, M.

doi:10.3109/1061186x.2015.1077847

Cited by 37 publications

(56 citation statements)

References 60 publications

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“…Last, iTEPs are recombinant proteins. Their sequences and physicochemical properties such as hydrophobicity, conjugation sites (cysteines), and spacer length between the conjugation sites are precisely controlled using genetic engineering [20]. Using genetic engineering, we generated a series of iTEPs in this study that differ in the number of cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

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An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors

et al. 2016

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Cancer stem cell (CSC) inhibitors are a new category of investigational drugs to treat metastasis. Salinomycin (Sali) is one of most studied CSC inhibitors and has reached clinical tests. Several drug carriers have been developed to improve efficacy of Sali. However, Sali has not been shown to inhibit metastasis from orthotopic tumors, the gold standard for metastasis. To fill this gap, we developed an immune-tolerant, elastin-like polypeptide (iTEP)-based nanoparticle (iTEP-Sali-ABA NP) that released 4-(aminomethyl)benzaldehyde-modified Sali (Sali-ABA) under acidic conditions. We found that the NP increased the area under the curve (AUC) of Sali-ABA by 30-fold and the tumor accumulation by 3.4-fold. Furthermore, no metastasis was detected in any of the mice given the NP. However, all the mice died of primary tumor burdens. To overcome primary tumor growth and improve the overall survival, we applied a combination therapy consisting of the iTEP-Sali-ABA NP and iTEP NP-delivered paclitaxel. This therapy effectively retarded primary tumor growth, and most importantly, improved the overall survival. In conclusion, delivery of Sali-ABA by the NP, alone or in combination with paclitaxel, was more effective than free Sali-ABA in decreasing metastasis and increasing survival. This iTEP-Sali-ABA NP represents a novel and clinically promising therapy to combat metastasis.

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Section: Discussionmentioning

confidence: 99%

“…This modified Sali, Sali-ABA, was then conjugated to our recently invented, immune-tolerant elastin-like polypeptides (iTEPs) to create iTEP-Sali-ABA [20]. Sali-ABA was confirmed to be released from the iTEP in a pH-dependent manner, and iTEP-Sali-ABA conjugates were selectively toxic to CSCs.…”

Section: Introductionmentioning

confidence: 99%

An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors

et al. 2016

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“…The development of cytotoxic T-lymphocyte vaccine carriers using the previously mentioned iTEPs has also been described[88]. In this manuscript, a diblock copolymer consisting of hydrophobic iTEP A and hydrophilic iTEP B was fused to pOVA containing the SIINFEKL epitope.…”

Section: Applicationsmentioning

confidence: 99%

“…Based on prior work in small animal models, ELPs also exhibit biocompatibility and low immunogenicity[85-87]. One study by Cho et al [88] involved the application of immune-tolerant elastin-like polypeptides (iTEPs) as cytotoxic T-lymphocyte vaccine carriers. iTEP design places an emphasis on humoral tolerance through the absence of epitopes that can bind T and B cells.…”

Section: Introductionmentioning

confidence: 99%

Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines

Despanie

Dhandhukia

Hamm‐Alvarez

et al. 2016

Journal of Controlled Release

135

104

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Elastin-like polypeptides (ELPs) constitute a genetically engineered class of ‘protein polymers’ derived from human tropoelastin. They exhibit a reversible phase separation whereby samples remain soluble below a transition temperature (Tt) but form amorphous coacervates above Tt. Their phase behavior has many possible applications in purification, sensing, activation, and nanoassembly. As humanized polypeptides, they are non-immunogenic, substrates for proteolytic biodegradation, and can be decorated with pharmacologically active peptides, proteins, and small molecules. Recombinant synthesis additionally allows precise control over ELP architecture and molecular weight, resulting in protein polymers with uniform physicochemical properties suited to the design of multifunctional biologics. As such, ELPs have been employed for various uses including as anti-cancer agents, ocular drug delivery vehicles, and protein trafficking modulators. This review aims to offer the reader a catalogue of ELPs, their various applications, and potential for commercialization across a broad spectrum of fields.

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“…Different from the previously reported carrier of the inhibitors 17 , αPD-1 and its carrier molecule, iTEP 18-20 , were generated together as a recombinant fusion protein. The fusion is able to self-assemble into a NP.…”

Section: Introductionmentioning

confidence: 99%

An Anti-Programmed Death-1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD-1 Nanoparticle

et al. 2017

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Cancer immune checkpoint therapy has achieved remarkable clinical successes in various cancers. However, current immune checkpoint inhibitors block the checkpoint of not only the immune cells that are important to cancer therapy but also the immune cells that are irrelevant to the therapy. Such an indiscriminate blockade limits the efficacy and causes the autoimmune toxicity of the therapy. It might be beneficial to use a carrier to target immune checkpoint inhibitors to cancer-reactive immune cells. Here, we explore a method to load the inhibitors into carriers. We used the anti-programmed death-1 antibody (αPD-1) as a model immune checkpoint inhibitor. First, we generated a recombinant single-chain variable fragment (scFv) of αPD-1. Then, we designed and generated a fusion protein consisting of the scFv and an amphiphilic immune-tolerant elastin-like polypeptide (iTEP). Because of the amphiphilic iTEP, the fusion was able to self-assemble into a nanoparticle (NP). The NP was proved to block the PD-1 immune checkpoint in vitro and in vivo. Particularly, the NP exacerbated diabetes development in non-obese diabetic mice as effectively as natural, intact αPD-1. In summary, we successfully expressed αPD-1 as a recombinant protein and linked αPD-1 to a NP, which lays a foundation to develop a delivery system to target αPD-1 to a subpopulation of immune cells.

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Immune-tolerant elastin-like polypeptides (iTEPs) and their application as CTL vaccine carriers

Cited by 37 publications

References 60 publications

An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors

An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors

Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines

An Anti-Programmed Death-1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD-1 Nanoparticle

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