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      Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer

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          Abstract

          Introduction

          The integration of diagnostic testing for the presence of a molecular target is of interest to predict successful targeted radionuclide therapy (TRNT). This so-called ‘theranostic’ approach aims to improve personalized treatment based on the molecular characteristics of cancer cells. Moreover, it offers new insights in predicting adverse effects and provides appropriate tools to monitor therapy responses. Recent findings using nanobodies emphasize their potential as theranostic tools in cancer treatment. Nanobodies are recombinant, small antigen-binding fragments that are derived from camelid heavy-chain-only antibodies.

          Areas covered

          We review the current status of theranostic approaches in TRNT, with a focus on antibodies, peptides, scaffold proteins and emerging nanobodies. In recent years, nanobodies have been evaluated intensively for molecular imaging. In addition, novel data on TRNT using radiolabeled nanobodies for carcinomas and multiple myeloma highlight their promising opportunities in cancer treatment.

          Expert opinion

          We trust that radiolabeled nanobodies will have a future potential as theranostic tools in cancer therapy, both for diagnosis as well as for TRNT.

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          Most cited references77

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          Novel cancer immunotherapy agents with survival benefit: recent successes and next steps.

          Padmanee Sharma, Klaus. Wagner, Jedd Wolchok … (2011)
          The US Food and Drug Administration (FDA) recently approved two novel immunotherapy agents, sipuleucel-T and ipilimumab, which showed a survival benefit for patients with metastatic prostate cancer and melanoma, respectively. The mechanisms by which these agents provideclinical benefit are not completely understood. However, knowledge of these mechanisms will be crucial for probing human immune responses and tumour biology in order to understand what distinguishes responders from non-responders. The following next steps are necessary: first, the development of immune-monitoring strategies for the identification of relevant biomarkers; second, the establishment of guidelines for the assessment of clinical end points; and third, the evaluation of combination therapy strategies to improve clinical benefit.
          Article 0 comments Cited 225 times – based on 0 reviews     Review now
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            Sequence and structure of VH domain from naturally occurring camel heavy chain immunoglobulins lacking light chains.

            S. Muyldermans, T. Atarhouch, J. Saldanha … (1994)
            We cloned 17 different PCR fragments encoding VH genes of camel (Camelus dromedarius). These clones were derived from the camel heavy chain immunoglobulins lacking the light chain counterpart of normal immunoglobulins. Insight into the camel VH sequences and structure may help the development of single domain antibodies. The most remarkable difference in the camel VH, consistent with the absence of the VL interaction, is the substitution of the conserved Leu45 by an Arg or Cys. Another noteworthy substitution is the Leu11 to Ser. This amino acid normally interacts with the CH1 domain, a domain missing in the camel heavy chain immunoglobulins. The nature of these substitutions agrees with the increased solubility behavior of an isolated camel VH domain. The VH domains of the camels are also characterized by a long CDR3, possibly compensating for the absence of the VL contacts with the antigen. The CDR3 lacks the salt bridge between Arg94 and Asp101. However, the frequent occurrence of additional Cys residues in both the CDR1 and CDR3 might lead to the formation of a second internal disulfide bridge, thereby stabilizing the CDR structure as in the DAW antibody. Within CDRs of the camel VH domains we observe a broad size distribution and a different amino acid pattern compared with the mouse or human VH. Therefore the camel hypervariable regions might adopt structures which differ substantially from the known canonical structures, thereby increasing the repertoire of the camel antigen binding sites within a VH.
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              Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages.

              Luc Bouwens, Jack van Loon, Wim Waelput … (2012)
              Tumor-associated macrophages (TAM) are an important component of the tumor stroma and exert several tumor-promoting activities. Strongly pro-angiogenic TAMs that reside in hypoxic tumor areas highly express macrophage mannose receptor (MMR, CD206). In this study, we targeted MMR+ TAMs using nanobodies, which are single-domain antigen-binding fragments derived from Camelidae heavy-chain antibodies. MMR-specific nanobodies stained TAMs in lung and breast tumor single-cell suspensions in vitro, and intravenous injection of 99mTc-labeled anti-MMR nanobodies successfully targeted tumor in vivo. Retention of the nanobody was receptor-specific and absent in MMR-deficient mice. Importantly, co-injection of excess unlabeled, bivalent anti-MMR nanobodies reduced nanobody accumulation in extratumoral organs to background levels, without compromising tumor uptake. Within tumors, the 99mTc-labeled nanobodies specifically labeled MMR+ TAMs, as CCR2-deficient mice that contain fewer TAMs showed significantly reduced tumor uptake. Further, anti-MMR nanobodies accumulated in hypoxic regions, thus targeting pro-angiogenic MMR+ TAMs. Taken together, our findings provide preclinical proof of concept that anti-MMR nanobodies can be used to selectively target and image TAM subpopulations in vivo. ©2012 AACR.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Expert Opin Drug Deliv
                Journal ID (iso-abbrev): Expert Opin Drug Deliv
                Journal ID (publisher-id): EDD
                Title: Expert Opinion on Drug Delivery
                Publisher: Informa UK, Ltd.
                ISSN (Print): 1742-5247
                ISSN (Electronic): 1744-7593
                Publication date (Print): December 2014
                Publication date (Electronic): 18 July 2014
                Volume: 11
                Issue: 12
                Pages: 1939-1954
                Affiliations
                1Belgian Nuclear Research Center (SCK·CEN), Radiobiology Unit, Molecular and Cellular Biology Expert Group , Mol, Belgium
                2Vrije Universiteit Brussel (VUB), In vivo Cellular and Molecular Imaging Laboratory (ICMI) , Laarbeeklaan 103, 1090 Brussels, Belgium
                3UZ Brussel, Department of Nuclear Medicine , Brussels, Belgium
                4Vrije Universiteit Brussel (VUB), Cellular and Molecular Immunology , Pleinlaan 2, 1050 Brussels, Belgium+32 2 6291969; svmuylde@ 123456vub.ac.be
                5Vlaams Instituut voor Biotechnologie (VIB), Structural Biology Research Center , Brussels, Belgium
                Author notes
                †Author for correspondence
                Article
                DOI: 10.1517/17425247.2014.941803
                PMC ID: 4245996
                PubMed ID: 25035968
                SO-VID: 36cdc0c6-0347-4a35-bf0f-fed42754c183
                Copyright © © Informa UK, Ltd.
                License:

                This is an open-access article distributed under the terms of the CC-BY-NC-ND 3.0 License which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is credited.

                History
                Categories
                Subject: Reviews
                Subject: Oncology

                Keywords: cancer,nanobody,nuclear imaging,radiochemistry,radionuclide,targeted radionuclide therapy,theranostics
                Data availability:
                Keywords: cancer, nanobody, nuclear imaging, radiochemistry, radionuclide, targeted radionuclide therapy, theranostics

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