Cargando…

In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model

IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge f...

Descripción completa

Detalles Bibliográficos
Autores principales: Williams, Iwan P., Crescioli, Silvia, Sow, Heng Sheng, Bax, Heather J., Hobbs, Carl, Ilieva, Kristina M., French, Elise, Pellizzari, Giulia, Cox, Vivienne, Josephs, Debra H., Spicer, James F., Karagiannis, Sophia N., Mele, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927758/
https://www.ncbi.nlm.nih.gov/pubmed/31769737
http://dx.doi.org/10.1080/19420862.2019.1685349
_version_ 1783482350722613248
author Williams, Iwan P.
Crescioli, Silvia
Sow, Heng Sheng
Bax, Heather J.
Hobbs, Carl
Ilieva, Kristina M.
French, Elise
Pellizzari, Giulia
Cox, Vivienne
Josephs, Debra H.
Spicer, James F.
Karagiannis, Sophia N.
Mele, Silvia
author_facet Williams, Iwan P.
Crescioli, Silvia
Sow, Heng Sheng
Bax, Heather J.
Hobbs, Carl
Ilieva, Kristina M.
French, Elise
Pellizzari, Giulia
Cox, Vivienne
Josephs, Debra H.
Spicer, James F.
Karagiannis, Sophia N.
Mele, Silvia
author_sort Williams, Iwan P.
collection PubMed
description IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.
format Online
Article
Text
id pubmed-6927758
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-69277582020-01-03 In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model Williams, Iwan P. Crescioli, Silvia Sow, Heng Sheng Bax, Heather J. Hobbs, Carl Ilieva, Kristina M. French, Elise Pellizzari, Giulia Cox, Vivienne Josephs, Debra H. Spicer, James F. Karagiannis, Sophia N. Mele, Silvia MAbs Report IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4. Taylor & Francis 2019-11-26 /pmc/articles/PMC6927758/ /pubmed/31769737 http://dx.doi.org/10.1080/19420862.2019.1685349 Text en © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Williams, Iwan P.
Crescioli, Silvia
Sow, Heng Sheng
Bax, Heather J.
Hobbs, Carl
Ilieva, Kristina M.
French, Elise
Pellizzari, Giulia
Cox, Vivienne
Josephs, Debra H.
Spicer, James F.
Karagiannis, Sophia N.
Mele, Silvia
In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title_full In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title_fullStr In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title_full_unstemmed In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title_short In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model
title_sort in vivo safety profile of a cspg4-directed ige antibody in an immunocompetent rat model
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927758/
https://www.ncbi.nlm.nih.gov/pubmed/31769737
http://dx.doi.org/10.1080/19420862.2019.1685349
work_keys_str_mv AT williamsiwanp invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT cresciolisilvia invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT sowhengsheng invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT baxheatherj invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT hobbscarl invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT ilievakristinam invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT frenchelise invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT pellizzarigiulia invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT coxvivienne invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT josephsdebrah invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT spicerjamesf invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT karagiannissophian invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel
AT melesilvia invivosafetyprofileofacspg4directedigeantibodyinanimmunocompetentratmodel