Drugs derived from phage display

Nixon, Andrew E.; Sexton, Daniel J.; Ladner, Robert C.

doi:10.4161/mabs.27240

Cited by 146 publications

(81 citation statements)

References 78 publications

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“…Antibody development has progressed from hybridoma technology to a recombinant deoxyribonucleic acid (DNA) approach. In the last few years, a number of engineered antibody drugs have been approved or investigated in phase II or III clinical trials ( Table 3; Nelson et al, 2010;Dantas-Barbosa et al, 2012;Nixon et al, 2014).…”

Section: Antibody Engineeringmentioning

confidence: 99%

Antibody Engineering for Pursuing a Healthier Future

et al. 2017

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Since the development of antibody-production techniques, a number of immunoglobulins have been developed on a large scale using conventional methods. Hybridoma technology opened a new horizon in the production of antibodies against target antigens of infectious pathogens, malignant diseases including autoimmune disorders, and numerous potent toxins. However, these clinical humanized or chimeric murine antibodies have several limitations and complexities. Therefore, to overcome these difficulties, recent advances in genetic engineering techniques and phage display technique have allowed the production of highly specific recombinant antibodies. These engineered antibodies have been constructed in the hunt for novel therapeutic drugs equipped with enhanced immunoprotective abilities, such as engaging immune effector functions, effective development of fusion proteins, efficient tumor and tissue penetration, and high-affinity antibodies directed against conserved targets. Advanced antibody engineering techniques have extensive applications in the fields of immunology, biotechnology, diagnostics, and therapeutic medicines. However, there is limited knowledge regarding dynamic antibody development approaches. Therefore, this review extends beyond our understanding of conventional polyclonal and monoclonal antibodies. Furthermore, recent advances in antibody engineering techniques together with antibody fragments, display technologies, immunomodulation, and broad applications of antibodies are discussed to enhance innovative antibody production in pursuit of a healthier future for humans.

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Section: Antibody Engineeringmentioning

confidence: 99%

Antibody Engineering for Pursuing a Healthier Future

et al. 2017

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“…The utility of phage display for developing lead compounds is well appreciated, with its proficiency deriving from the ability to make and screen libraries of up to 10 12 sequences and the linkage of genotype to binding phenotype [46]. Typical peptide phage display involves the creation of large libraries sampling enormous sequentially continuous sequence space on unstructured peptides that assume structure only upon binding the target bait.…”

Section: Discussionmentioning

confidence: 99%

Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23

et al. 2016

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BackgroundDisulfide-rich peptides (DRPs) are found throughout nature. They are suitable scaffolds for drug development due to their small cores, whose disulfide bonds impart extraordinary chemical and biological stability. A challenge in developing a DRP therapeutic is to engineer binding to a specific target. This challenge can be overcome by (i) sampling the large sequence space of a given scaffold through a phage display library and by (ii) panning multiple libraries encoding structurally distinct scaffolds. Here, we implement a protocol for defining these diverse scaffolds, based on clustering structurally defined DRPs according to their conformational similarity.ResultsWe developed and applied a hierarchical clustering protocol based on DRP structural similarity, followed by two post-processing steps, to classify 806 unique DRP structures into 81 clusters. The 20 most populated clusters comprised 85% of all DRPs. Representative scaffolds were selected from each of these clusters; the representatives were structurally distinct from one another, but similar to other DRPs in their respective clusters. To demonstrate the utility of the clusters, phage libraries were constructed for three of the representative scaffolds and panned against interleukin-23. One library produced a peptide that bound to this target with an IC50 of 3.3 μM.ConclusionsMost DRP clusters contained members that were diverse in sequence, host organism, and interacting proteins, indicating that cluster members were functionally diverse despite having similar structure. Only 20 peptide scaffolds accounted for most of the natural DRP structural diversity, providing suitable starting points for seeding phage display experiments. Through selection of the scaffold surface to vary in phage display, libraries can be designed that present sequence diversity in architecturally distinct, biologically relevant combinations of secondary structures. We supported this hypothesis with a proof-of-concept experiment in which three phage libraries were constructed and panned against the IL-23 target, resulting in a single-digit μM hit and suggesting that a collection of libraries based on the full set of 20 scaffolds increases the potential to identify efficiently peptide binders to a protein target in a drug discovery program.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1350-9) contains supplementary material, which is available to authorized users.

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“…In principle, antibodies can be produced from cultured cells [119], and can be engineered [120] or selected [121, 122] against any target protein to regulate its downstream effect. Nevertheless, for decades the hybridoma technique developed by Köhler and Milstein was the only reliable method to produce mAbs from splenocytes isolated from mice immunized with a target antigen.…”

Section: Targeting Strategiesmentioning

confidence: 99%

Ligand-targeted theranostic nanomedicines against cancer

Yao¹,

D’Angelo²,

Butler

et al. 2016

Journal of Controlled Release

169

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Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.

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Drugs derived from phage display

Cited by 146 publications

References 78 publications

Antibody Engineering for Pursuing a Healthier Future

Antibody Engineering for Pursuing a Healthier Future

Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23

Ligand-targeted theranostic nanomedicines against cancer

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