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Antibody Therapeutics
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  This is an Open Access Journal Open Access journal
ISSN (Online) 2516-4236
Published by Oxford University Press Homepage  [406 journals]
  • T-cell receptor mimic (TCRm) antibody therapeutics against intracellular

    • Authors: Xu Y; Salazar G, Zhang N, et al.
      Abstract: AbstractT-cell receptor mimic (TCRm) antibodies combine the capacity of a T cell to target intracellular antigens with other capacities unique to antibodies. Neoantigens are abnormal proteins that arise as a consequence of somatic mutations. Technological advances promote the development of neoantigen-targeting therapies including TCRm antibody therapies. This review summarizes key characteristics of TCRm antibodies, in particular those targeting neoantigens, and further introduces discussion of obstacles that must be overcome to advance TCRm therapeutics.
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
  • Generation of antibody-based therapeutics targeting the idiotype of B-cell

    • Authors: Weiss E; Sarnovsky R, Ho M, et al.
      Abstract: ABSTRACTBackgroundA feature of many B-cell tumors is a surface-expressed immunoglobulin (sIg). The complementarity-determining regions (CDRs) of the sIg, termed the ‘idiotype’, are unique to each tumor. We report on a phage selection strategy to generate anti-idiotype therapeutics that reacts with sIg CDR3 sequences; the MEC1 B-cell tumor line was used as proof of concept.MethodsTo create a mimetic of the MEC1 idiotype, CDR3 sequences from heavy and light chains of the sIg were grafted into a single chain variable fragment (scFv) framework scaffold. Using the Tomlinson I phage library of human scFvs, we enriched for binders to MEC1 CDR3 sequences over unrelated CDR3 sequences.ResultsBy ELISA we identified 10 binder phages. Of these, five were sequenced, found to be unique and characterized further. By flow cytometry each of the five phages bound to MEC1 cells, albeit with different patterns of reactivity. To establish specificity of binding and utility, the scFv sequences from two of these binders (phages 1 and 7) were converted into antibody-toxin fusion proteins (immunotoxins) and also cloned into a human IgG1 expression vector. Binders 1 and 7 immunotoxins exhibited specific killing of MEC1 cells with little toxicity for non-target B-cell lines. The full-length antibody recreated from the binder-1 scFv also exhibited specific binding.ConclusionOur results establish the utility of using engrafted CDR3 sequences for selecting phage that recognize the idiotype of B-cell tumors.
      PubDate: Thu, 27 Dec 2018 00:00:00 GMT
  • Construction and next-generation sequencing analysis of a large
           phage-displayed VNAR single-domain antibody library from six na├»ve nurse

    • Authors: Feng M; Bian H, Wu X, et al.
      Abstract: ABSTRACTBackground: Shark new antigen receptor variable domain (VNAR) antibodies can bind restricted epitopes that may be inaccessible to conventional antibodies.Methods: Here, we developed a library construction method based on polymerase chain reaction (PCR)-Extension Assembly and Self-Ligation (named “EASeL”) to construct a large VNAR antibody library with a size of 1.2 × 1010 from six naïve adult nurse sharks (Ginglymostoma cirratum).Results: The next-generation sequencing analysis of 1.19 million full-length VNARs revealed that this library is highly diversified because it covers all four classical VNAR types (Types I–IV) including 11% of classical Type I and 57% of classical Type II. About 30% of the total VNARs could not be categorized as any of the classical types. The high variability of complementarity determining region (CDR) 3 length and cysteine numbers are important for the diversity of VNARs. To validate the use of the shark VNAR library for antibody discovery, we isolated a panel of VNAR phage binders to cancer therapy-related antigens, including glypican-3, human epidermal growth factor receptor 2 (HER2), and programmed cell death-1 (PD1). Additionally, we identified binders to viral antigens that included the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) spike proteins. The isolated shark single-domain antibodies including Type I and Type II VNARs were produced in Escherichia coli and validated for their antigen binding. A Type II VNAR (PE38-B6) has a high affinity (Kd = 10.1 nM) for its antigen.Conclusions: The naïve nurse shark VNAR library is a useful source for isolating single-domain antibodies to a wide range of antigens. The EASeL method may be applicable to the construction of other large diversity gene expression libraries.Statement of SignificanceA method called “EASeL” for overlap extension PCR combined with self-ligation has been established for constructing a large phage-displayed VNAR single-domain antibody library from six nurse sharks. The shark single-domain library provides an alternative platform for selecting therapeutic antibodies for treating cancer and other human diseases.
      PubDate: Wed, 07 Nov 2018 00:00:00 GMT
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