Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment
Monoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, div...
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doaj-31d0174881e947029761ba0141a008312020-11-24T20:54:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-02-01910.3389/fimmu.2018.00273307791Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and TreatmentMaría Elena Iezzi0Lucía Policastro1Lucía Policastro2Santiago Werbajh3Osvaldo Podhajcer4Gabriela Alicia Canziani5Laboratorio de Terapia Molecular y Celular, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Ciudad Autónoma de Buenos Aires, ArgentinaLaboratorio de Terapia Molecular y Celular, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Ciudad Autónoma de Buenos Aires, ArgentinaLaboratorio Nanomedicina, Gerencia de Desarrollo Tecnológico y Proyectos Especiales, Comisión Nacional de Energía Atómica, Ciudad Autónoma de Buenos Aires, ArgentinaLaboratorio de Terapia Molecular y Celular, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Ciudad Autónoma de Buenos Aires, ArgentinaLaboratorio de Terapia Molecular y Celular, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Ciudad Autónoma de Buenos Aires, ArgentinaLaboratorio de Terapia Molecular y Celular, Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA-CONICET), Ciudad Autónoma de Buenos Aires, ArgentinaMonoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, diversity, and complexity of validated tumor targets there is an increasing focus on engineering recombinant antibody fragments for lead development. Single-domain antibodies (sdAbs), in particular those engineered from the variable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies (or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacity of the antibody with advantageous properties as drugs. For similar reasons, growing attention is being paid to the yet smaller variable heavy chain new antigen receptor (VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immune VHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cell membrane receptors, or block cytoplasmic targets. This succinct review is a compilation of recent data documenting the application of engineered, recombinant sdAb in the clinic as epitope recognition “modules” to build monomeric, dimeric and multimeric ligands that target, tag and stall solid tumor growth in vivo. Size, affinity, specificity, and the development profile of sdAbs drugs are seemingly consistent with desirable clinical efficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHH drug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial and called for a thorough pre-screening of the immune and poly-specific reactivities of the sdAb leads.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00273/fullcamelid heavy-chain antibodydrug-like propertiesbioavailabilityimmunogenicitybroad epitope coveragepoly-specificity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
María Elena Iezzi Lucía Policastro Lucía Policastro Santiago Werbajh Osvaldo Podhajcer Gabriela Alicia Canziani |
spellingShingle |
María Elena Iezzi Lucía Policastro Lucía Policastro Santiago Werbajh Osvaldo Podhajcer Gabriela Alicia Canziani Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment Frontiers in Immunology camelid heavy-chain antibody drug-like properties bioavailability immunogenicity broad epitope coverage poly-specificity |
author_facet |
María Elena Iezzi Lucía Policastro Lucía Policastro Santiago Werbajh Osvaldo Podhajcer Gabriela Alicia Canziani |
author_sort |
María Elena Iezzi |
title |
Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment |
title_short |
Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment |
title_full |
Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment |
title_fullStr |
Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment |
title_full_unstemmed |
Single-Domain Antibodies and the Promise of Modular Targeting in Cancer Imaging and Treatment |
title_sort |
single-domain antibodies and the promise of modular targeting in cancer imaging and treatment |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-02-01 |
description |
Monoclonal antibodies and their fragments have significantly changed the outcome of cancer in the clinic, effectively inhibiting tumor cell proliferation, triggering antibody-dependent immune effector cell activation and complement mediated cell death. Along with a continued expansion in number, diversity, and complexity of validated tumor targets there is an increasing focus on engineering recombinant antibody fragments for lead development. Single-domain antibodies (sdAbs), in particular those engineered from the variable heavy-chain fragment (VHH gene) found in Camelidae heavy-chain antibodies (or IgG2 and IgG3), are the smallest fragments that retain the full antigen-binding capacity of the antibody with advantageous properties as drugs. For similar reasons, growing attention is being paid to the yet smaller variable heavy chain new antigen receptor (VNAR) fragments found in Squalidae. sdAbs have been selected, mostly from immune VHH libraries, to inhibit or modulate enzyme activity, bind soluble factors, internalize cell membrane receptors, or block cytoplasmic targets. This succinct review is a compilation of recent data documenting the application of engineered, recombinant sdAb in the clinic as epitope recognition “modules” to build monomeric, dimeric and multimeric ligands that target, tag and stall solid tumor growth in vivo. Size, affinity, specificity, and the development profile of sdAbs drugs are seemingly consistent with desirable clinical efficacy and safety requirements. But the hepatotoxicity of the tetrameric anti-DR5-VHH drug in patients with pre-existing anti-drug antibodies halted the phase I clinical trial and called for a thorough pre-screening of the immune and poly-specific reactivities of the sdAb leads. |
topic |
camelid heavy-chain antibody drug-like properties bioavailability immunogenicity broad epitope coverage poly-specificity |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2018.00273/full |
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