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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2019.1685349 |
| _version_ | 1817989216910442496 |
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| author | Iwan P. Williams Silvia Crescioli Heng Sheng Sow Heather J. Bax Carl Hobbs Kristina M. Ilieva Elise French Giulia Pellizzari Vivienne Cox Debra H. Josephs James F. Spicer Sophia N. Karagiannis Silvia Mele |
| author_facet | Iwan P. Williams Silvia Crescioli Heng Sheng Sow Heather J. Bax Carl Hobbs Kristina M. Ilieva Elise French Giulia Pellizzari Vivienne Cox Debra H. Josephs James F. Spicer Sophia N. Karagiannis Silvia Mele |
| author_sort | Iwan P. Williams |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-14T00:44:20Z |
| format | Article |
| id | doaj.art-6ff446d9996240a9913b11d5fd13c531 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-04-14T00:44:20Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-6ff446d9996240a9913b11d5fd13c5312022-12-22T02:22:05ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2019.1685349In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat modelIwan P. Williams0Silvia Crescioli1Heng Sheng Sow2Heather J. Bax3Carl Hobbs4Kristina M. Ilieva5Elise French6Giulia Pellizzari7Vivienne Cox8Debra H. Josephs9James F. Spicer10Sophia N. Karagiannis11Silvia Mele12St John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKWolfson Centre for Age-Related Diseases, King’s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKIGEM Therapeutics Ltd, London BioScience Innovation Centre, London, UKSchool of Cancer & Pharmaceutical Sciences, King’s College London, Bermondsey Wing, Guy’s Hospital, Bermondsey Wing, London, UKSchool of Cancer & Pharmaceutical Sciences, King’s College London, Bermondsey Wing, Guy’s Hospital, Bermondsey Wing, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKSt John`s Institute of Dermatology, School of Basic and Medical Biosciences, King`s College London, London, UKIgE 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.https://www.tandfonline.com/doi/10.1080/19420862.2019.1685349IgErat modelimmunotherapyallergooncologyCSPG4antibody |
| spellingShingle | Iwan P. Williams Silvia Crescioli Heng Sheng Sow Heather J. Bax Carl Hobbs Kristina M. Ilieva Elise French Giulia Pellizzari Vivienne Cox Debra H. Josephs James F. Spicer Sophia N. Karagiannis Silvia Mele In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model mAbs IgE rat model immunotherapy allergooncology CSPG4 antibody |
| 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 | IgE rat model immunotherapy allergooncology CSPG4 antibody |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2019.1685349 |
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