Camelid and shark single domain antibodies: structural features and therapeutic potential.

In addition to canonical antibodies composed of heavy and light chains, the adaptive immune systems of camelids and cartilaginous fish comprise heavy-chain only isotypes (HcAb) devoid of light chains, where antigen-binding is mediated exclusively by one variable domain. Due to their inherent favorable attributes, such as high affinity and specificity for their cognate antigen, extraordinary stability, small size and, most importantly, the possibility to complement classical antibodies in terms of 'drugable' target-space, HcAb-derived entities evolved as promising candidates for biomedical applications of which many have already proven to be successful in early stage clinical trials.

[1]  Shenghua Li,et al.  Selection of hapten-specific single-domain antibodies from a non-immunized llama ribosome display library. , 2003, Journal of immunological methods.

[2]  A. Christmann,et al.  Shark Attack: high affinity binding proteins derived from shark vNAR domains by stepwise in vitro affinity maturation. , 2014, Journal of biotechnology.

[3]  Brian J. Raney,et al.  Elephant shark genome provides unique insights into gnathostome evolution , 2014, Nature.

[4]  M. Flajnik,et al.  VNAR single-domain antibodies specific for BAFF inhibit B cell development by molecular mimicry. , 2016, Molecular immunology.

[5]  M. Rajabibazl,et al.  Production of Novel VHH Nanobody Inhibiting Angiogenesis by Targeting Binding Site of VEGF , 2015, Applied Biochemistry and Biotechnology.

[6]  Yakun Wan,et al.  Construction of a synthetic phage-displayed Nanobody library with CDR3 regions randomized by trinucleotide cassettes for diagnostic applications , 2014, Journal of Translational Medicine.

[7]  Austin Hughes,et al.  A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks , 1995, Nature.

[8]  M. Smit,et al.  GPCR-targeting nanobodies: attractive research tools, diagnostics, and therapeutics. , 2014, Trends in pharmacological sciences.

[9]  W. Sellers,et al.  Multivalent nanobodies targeting death receptor 5 elicit superior tumor cell killing through efficient caspase induction , 2014, mAbs.

[10]  Simon J. Henderson,et al.  Monoclonal antibody therapeutics: history and future. , 2012, Current opinion in pharmacology.

[11]  R. Márquez-Velasco,et al.  Anti-tumor necrosis factor VNAR single domains reduce lethality and regulate underlying inflammatory response in a murine model of endotoxic shock , 2013, BMC Immunology.

[12]  L. Mosyak,et al.  Atypical Antigen Recognition Mode of a Shark Immunoglobulin New Antigen Receptor (IgNAR) Variable Domain Characterized by Humanization and Structural Analysis , 2013, The Journal of Biological Chemistry.

[13]  S. Achilefu,et al.  Small Sized EGFR1 and HER2 Specific Bifunctional Antibody for Targeted Cancer Therapy , 2015, Theranostics.

[14]  S. Muyldermans,et al.  Surface display of a single-domain antibody library on Gram-positive bacteria , 2012, Cellular and Molecular Life Sciences.

[15]  M. Flajnik,et al.  An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Papadopoulos,et al.  Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor , 2015, Cancer Chemotherapy and Pharmacology.

[17]  M. Flajnik,et al.  Isolation and characterisation of Ebolavirus-specific recombinant antibody fragments from murine and shark immune libraries. , 2011, Molecular immunology.

[18]  H. Kolmar,et al.  The Shark Strikes Twice: Hypervariable Loop 2 of Shark IgNAR Antibody Variable Domains and Its Potential to Function as an Autonomous Paratope , 2015, Marine Biotechnology.

[19]  L. Wyns,et al.  Selection and identification of single domain antibody fragments from camel heavy‐chain antibodies , 1997, FEBS letters.

[20]  I. Wilson,et al.  Maturation of shark single-domain (IgNAR) antibodies: evidence for induced-fit binding. , 2007, Journal of molecular biology.

[21]  I. Vernos,et al.  Allosteric inhibition of Aurora-A kinase by a synthetic VNAR nanobody , 2016, bioRxiv.

[22]  N. Callewaert,et al.  Isolation of antigen-binding camelid heavy chain antibody fragments (nanobodies) from an immune library displayed on the surface of Pichia pastoris. , 2010, Journal of biotechnology.

[23]  Michael Sattler,et al.  The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins , 2014, Proceedings of the National Academy of Sciences.

[24]  I. Hirono,et al.  Variable domain antibodies specific for viral hemorrhagic septicemia virus (VHSV) selected from a randomized IgNAR phage display library. , 2013, Fish & shellfish immunology.

[25]  Robyn L Stanfield,et al.  First molecular and biochemical analysis of in vivo affinity maturation in an ectothermic vertebrate. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Foley,et al.  Selection and affinity maturation of IgNAR variable domains targeting Plasmodium falciparum AMA1 , 2004, Proteins.

[27]  M. Flajnik,et al.  Structural analysis, selection, and ontogeny of the shark new antigen receptor (IgNAR): identification of a new locus preferentially expressed in early development , 2002, Immunogenetics.

[28]  B. '. ’t Hart,et al.  The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis , 2015, Arthritis Research & Therapy.

[29]  Lode Wyns,et al.  Crystal structure of a camel single-domain VH antibody fragment in complex with lysozyme , 1996, Nature Structural Biology.

[30]  I. Wilson,et al.  Crystal Structure of a Shark Single-Domain Antibody V Region in Complex with Lysozyme , 2004, Science.

[31]  Lode Wyns,et al.  Potent enzyme inhibitors derived from dromedary heavy‐chain antibodies , 1998, The EMBO journal.

[32]  James B Delehanty,et al.  Facile generation of heat-stable antiviral and antitoxin single domain antibodies from a semisynthetic llama library. , 2006, Analytical chemistry.

[33]  C. Barelle,et al.  Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development , 2014, Expert opinion on biological therapy.

[34]  C. Barelle,et al.  VNARs: An Ancient and Unique Repertoire of Molecules That Deliver Small, Soluble, Stable and High Affinity Binders of Proteins , 2015 .

[35]  M. Criscitiello.  What the shark immune system can and cannot provide for the expanding design landscape of immunotherapy , 2014, Expert opinion on drug discovery.

[36]  S. Muyldermans,et al.  General Strategy to Humanize a Camelid Single-domain Antibody and Identification of a Universal Humanized Nanobody Scaffold* , 2009, Journal of Biological Chemistry.

[37]  J. Reichert.  Antibodies to watch in 2016 , 2016, mAbs.

[38]  H. Kolmar,et al.  Isolation of a pH-Sensitive IgNAR Variable Domain from a Yeast-Displayed, Histidine-Doped Master Library , 2016, Marine Biotechnology.

[39]  A. D. de Fougerolles,et al.  Nanobodies®† as inhaled biotherapeutics for lung diseases , 2017, Pharmacology & therapeutics.

[40]  P. Hudson,et al.  Isolation and characterization of an IgNAR variable domain specific for the human mitochondrial translocase receptor Tom70. , 2003, European journal of biochemistry.

[41]  B. Jilma,et al.  Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. , 2016, The New England journal of medicine.

[42]  D. Ecker,et al.  The therapeutic monoclonal antibody market , 2015, mAbs.

[43]  C. Palomo,et al.  Generation and Characterization of ALX-0171, a Potent Novel Therapeutic Nanobody for the Treatment of Respiratory Syncytial Virus Infection , 2015, Antimicrobial Agents and Chemotherapy.

[44]  C. Secombes,et al.  Rapid isolation of IgNAR variable single-domain antibody fragments from a shark synthetic library. , 2007, Molecular immunology.

[45]  S. Muyldermans,et al.  Sequence and structure of VH domain from naturally occurring camel heavy chain immunoglobulins lacking light chains. , 1994, Protein engineering.

[46]  Olan Dolezal,et al.  i-bodies, Human Single Domain Antibodies That Antagonize Chemokine Receptor CXCR4* , 2016, The Journal of Biological Chemistry.

[47]  S. Nuttall,et al.  Display scaffolds: protein engineering for novel therapeutics. , 2008, Current opinion in pharmacology.

[48]  C. Francavilla,et al.  Immunological applications of single-domain llama recombinant antibodies isolated from a naïve library. , 2009, Protein engineering, design & selection : PEDS.

[49]  Andrew J Porter,et al.  Selection and characterization of naturally occurring single-domain (IgNAR) antibody fragments from immunized sharks by phage display. , 2003, Molecular immunology.

[50]  O. Dolezal,et al.  Targeting the hepatitis B virus precore antigen with a novel IgNAR single variable domain intrabody. , 2011, Virology.

[51]  M. Flajnik,et al.  The plasticity of immunoglobulin gene systems in evolution , 2006, Immunological reviews.

[52]  M. Seman,et al.  Single domain antibodies: promising experimental and therapeutic tools in infection and immunity , 2009, Medical Microbiology and Immunology.

[53]  Nick Deschacht,et al.  A Case Of Convergence: Why Did a Simple Alternative to Canonical Antibodies Arise in Sharks and Camels? , 2011, PLoS biology.

[54]  E. Goldman,et al.  Isolation of anti-toxin single domain antibodies from a semi-synthetic spiny dogfish shark display library , 2007, BMC biotechnology.

[55]  M. Flajnik,et al.  A shark antibody heavy chain encoded by a nonsomatically rearranged VDJ is preferentially expressed in early development and is convergent with mammalian IgG. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Harald Kolmar,et al.  Single-domain antibodies for biomedical applications , 2016, Immunopharmacology and immunotoxicology.

[57]  S. Muyldermans,et al.  Naturally occurring antibodies devoid of light chains , 1993, Nature.

[58]  R. Leurs,et al.  CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells , 2010, Proceedings of the National Academy of Sciences.

[59]  James B Delehanty,et al.  Selection of cholera toxin specific IgNAR single-domain antibodies from a naïve shark library. , 2007, Molecular immunology.

[60]  Y. Vugmeyster,et al.  Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain , 2012, mAbs.

[61]  Serge Muyldermans,et al.  Distinct antibody species: structural differences creating therapeutic opportunities. , 2016, Current opinion in immunology.

[62]  J. Holz.  The TITAN trial--assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura. , 2012, Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis.

[63]  V. Streltsov,et al.  Structure of a shark IgNAR antibody variable domain and modeling of an early‐developmental isotype , 2005, Protein science : a publication of the Protein Society.

[64]  G. V. van Dongen,et al.  Llama-derived Single Variable Domains (Nanobodies) Directed against Chemokine Receptor CXCR7 Reduce Head and Neck Cancer Cell Growth in Vivo , 2013, The Journal of Biological Chemistry.

[65]  C. Barelle,et al.  Shark novel antigen receptors--the next generation of biologic therapeutics? , 2009, Advances in experimental medicine and biology.

[66]  H. Kolmar,et al.  Structural insights and biomedical potential of IgNAR scaffolds from sharks , 2014, mAbs.