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Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement
Monoclonal anti-programmed cell death 1 (PD1) antibodies are successful cancer therapeutics, but it is not well understood why individual antibodies should have idiosyncratic side-effects. As the humanized antibody SHR-1210 causes capillary hemangioma in patients, a unique toxicity amongst anti-PD1...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343799/ https://www.ncbi.nlm.nih.gov/pubmed/30541416 http://dx.doi.org/10.1080/19420862.2018.1550321 |
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author | Finlay, William J.J. Coleman, James E. Edwards, Jonathan S. Johnson, Kevin S. |
author_facet | Finlay, William J.J. Coleman, James E. Edwards, Jonathan S. Johnson, Kevin S. |
author_sort | Finlay, William J.J. |
collection | PubMed |
description | Monoclonal anti-programmed cell death 1 (PD1) antibodies are successful cancer therapeutics, but it is not well understood why individual antibodies should have idiosyncratic side-effects. As the humanized antibody SHR-1210 causes capillary hemangioma in patients, a unique toxicity amongst anti-PD1 antibodies, we performed human receptor proteome screening to identify nonspecific interactions that might drive angiogenesis. This screen identified that SHR-1210 mediated aberrant, but highly selective, low affinity binding to human receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), frizzled class receptor 5 and UL16 binding protein 2 (ULBP2). SHR-1210 was found to be a potent agonist of human VEGFR2, which may thereby drive hemangioma development via vascular endothelial cell activation. The v-domains of SHR-1210’s progenitor murine monoclonal antibody ‘Mab005ʹ also exhibited off-target binding and agonism of VEGFR2, proving that the polyspecificity was mediated by the original mouse complementarity-determining regions (CDRs), and had survived the humanization process. Molecular remodelling of SHR-1210 by combinatorial CDR mutagenesis led to deimmunization, normalization of binding affinity to human and cynomolgus PD1, and increased potency in PD1/PD-L1 blockade. Importantly, CDR optimization also ablated all off-target binding, rendering the resulting antibodies fully PD1-specific. As the majority of changes to the paratope were found in the light chain CDRs, the germlining of this domain drove the ablation of off-target binding. The combination of receptor proteome screening and optimization of the antibody binding interface therefore succeeded in generating novel, higher-potency, specificity-enhanced therapeutic IgGs from a single, clinically sub-optimal progenitor. This study showed that highly-specific off-target binding events might be an under-appreciated phenomenon in therapeutic antibody development, but that these unwanted properties can be fully ameliorated by paratope refinement. |
format | Online Article Text |
id | pubmed-6343799 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-63437992019-02-01 Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement Finlay, William J.J. Coleman, James E. Edwards, Jonathan S. Johnson, Kevin S. MAbs Report Monoclonal anti-programmed cell death 1 (PD1) antibodies are successful cancer therapeutics, but it is not well understood why individual antibodies should have idiosyncratic side-effects. As the humanized antibody SHR-1210 causes capillary hemangioma in patients, a unique toxicity amongst anti-PD1 antibodies, we performed human receptor proteome screening to identify nonspecific interactions that might drive angiogenesis. This screen identified that SHR-1210 mediated aberrant, but highly selective, low affinity binding to human receptors such as vascular endothelial growth factor receptor 2 (VEGFR2), frizzled class receptor 5 and UL16 binding protein 2 (ULBP2). SHR-1210 was found to be a potent agonist of human VEGFR2, which may thereby drive hemangioma development via vascular endothelial cell activation. The v-domains of SHR-1210’s progenitor murine monoclonal antibody ‘Mab005ʹ also exhibited off-target binding and agonism of VEGFR2, proving that the polyspecificity was mediated by the original mouse complementarity-determining regions (CDRs), and had survived the humanization process. Molecular remodelling of SHR-1210 by combinatorial CDR mutagenesis led to deimmunization, normalization of binding affinity to human and cynomolgus PD1, and increased potency in PD1/PD-L1 blockade. Importantly, CDR optimization also ablated all off-target binding, rendering the resulting antibodies fully PD1-specific. As the majority of changes to the paratope were found in the light chain CDRs, the germlining of this domain drove the ablation of off-target binding. The combination of receptor proteome screening and optimization of the antibody binding interface therefore succeeded in generating novel, higher-potency, specificity-enhanced therapeutic IgGs from a single, clinically sub-optimal progenitor. This study showed that highly-specific off-target binding events might be an under-appreciated phenomenon in therapeutic antibody development, but that these unwanted properties can be fully ameliorated by paratope refinement. Taylor & Francis 2018-12-12 /pmc/articles/PMC6343799/ /pubmed/30541416 http://dx.doi.org/10.1080/19420862.2018.1550321 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Report Finlay, William J.J. Coleman, James E. Edwards, Jonathan S. Johnson, Kevin S. Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title | Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title_full | Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title_fullStr | Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title_full_unstemmed | Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title_short | Anti-PD1 ‘SHR-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
title_sort | anti-pd1 ‘shr-1210ʹ aberrantly targets pro-angiogenic receptors and this polyspecificity can be ablated by paratope refinement |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343799/ https://www.ncbi.nlm.nih.gov/pubmed/30541416 http://dx.doi.org/10.1080/19420862.2018.1550321 |
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