Cargando…

Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma

ABSTRACT: Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (FcγRs) play important roles in regulating antibody-mediated immunity. FcγRIIB, the unique i...

Descripción completa

Detalles Bibliográficos
Autores principales: Jiang, Vivian Changying, Liu, Yang, Jordan, Alexa, Leeming, Angela, McIntosh, Joseph, Huang, Shengjian, Zhang, Rongjia, Cai, Qingsong, Chen, Zhihong, Li, Yijing, Che, Yuxuan, Nie, Lei, Karlsson, Ingrid, Mårtensson, Linda, Kovacek, Mathilda, Teige, Ingrid, Frendéus, Björn, Wang, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996600/
https://www.ncbi.nlm.nih.gov/pubmed/35410313
http://dx.doi.org/10.1186/s13045-022-01257-9
_version_ 1784684520392359936
author Jiang, Vivian Changying
Liu, Yang
Jordan, Alexa
Leeming, Angela
McIntosh, Joseph
Huang, Shengjian
Zhang, Rongjia
Cai, Qingsong
Chen, Zhihong
Li, Yijing
Che, Yuxuan
Nie, Lei
Karlsson, Ingrid
Mårtensson, Linda
Kovacek, Mathilda
Teige, Ingrid
Frendéus, Björn
Wang, Michael
author_facet Jiang, Vivian Changying
Liu, Yang
Jordan, Alexa
Leeming, Angela
McIntosh, Joseph
Huang, Shengjian
Zhang, Rongjia
Cai, Qingsong
Chen, Zhihong
Li, Yijing
Che, Yuxuan
Nie, Lei
Karlsson, Ingrid
Mårtensson, Linda
Kovacek, Mathilda
Teige, Ingrid
Frendéus, Björn
Wang, Michael
author_sort Jiang, Vivian Changying
collection PubMed
description ABSTRACT: Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (FcγRs) play important roles in regulating antibody-mediated immunity. FcγRIIB, the unique immune-checkpoint inhibitory member of the FcγR family, has been implicated in immune cell desensitization and tumor cell resistance to the anti-CD20 antibody rituximab and other antibody-mediated immunotherapies; however, little is known about its expression and its immune-modulatory function in patients with aggressive MCL, especially those with multi-resistance. In this study, we found that FcγRIIB was ubiquitously expressed in both MCL cell lines and primary patient samples. FcγRIIB expression is significantly higher in CAR T-relapsed patient samples (p < 0.0001) compared to ibrutinib/rituximab-naïve, sensitive or resistant samples. Rituximab-induced CD20 internalization in JeKo-1 cells was completely blocked by concurrent treatment with BI-1206, a recombinant human monoclonal antibody targeting FcγRIIB. Combinational therapies with rituximab-ibrutinib, rituximab-venetoclax and rituximab-CHOP also induced CD20 internalization which was again effectively blocked by BI-1206. BI-1206 significantly enhanced the in vivo anti-MCL efficacy of rituximab-ibrutinib (p = 0.05) and rituximab-venetoclax (p = 0.02), but not the rituximab-CHOP combination in JeKo-1 cell line-derived xenograft models. In patient-derived xenograft (PDX) models, BI-1206, as a single agent, showed high potency (p < 0.0001, compared to vehicle control) in one aggressive PDX model that is resistant to both ibrutinib and venetoclax but sensitive to the combination of rituximab and lenalidomide (the preclinical mimetic of R(2) therapy). BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p = 0.030). Moreover, BI-1206 significantly enhanced the efficacy of the rituximab-venetoclax combination (p < 0.05), which led to long-term tumor remission in 25% of mice. Altogether, these data support that targeting this new immune-checkpoint blockade enhances the therapeutic activity of rituximab-based regimens in aggressive MCL models with multi-resistance. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01257-9.
format Online
Article
Text
id pubmed-8996600
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-89966002022-04-12 Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma Jiang, Vivian Changying Liu, Yang Jordan, Alexa Leeming, Angela McIntosh, Joseph Huang, Shengjian Zhang, Rongjia Cai, Qingsong Chen, Zhihong Li, Yijing Che, Yuxuan Nie, Lei Karlsson, Ingrid Mårtensson, Linda Kovacek, Mathilda Teige, Ingrid Frendéus, Björn Wang, Michael J Hematol Oncol Letter to the Editor ABSTRACT: Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (FcγRs) play important roles in regulating antibody-mediated immunity. FcγRIIB, the unique immune-checkpoint inhibitory member of the FcγR family, has been implicated in immune cell desensitization and tumor cell resistance to the anti-CD20 antibody rituximab and other antibody-mediated immunotherapies; however, little is known about its expression and its immune-modulatory function in patients with aggressive MCL, especially those with multi-resistance. In this study, we found that FcγRIIB was ubiquitously expressed in both MCL cell lines and primary patient samples. FcγRIIB expression is significantly higher in CAR T-relapsed patient samples (p < 0.0001) compared to ibrutinib/rituximab-naïve, sensitive or resistant samples. Rituximab-induced CD20 internalization in JeKo-1 cells was completely blocked by concurrent treatment with BI-1206, a recombinant human monoclonal antibody targeting FcγRIIB. Combinational therapies with rituximab-ibrutinib, rituximab-venetoclax and rituximab-CHOP also induced CD20 internalization which was again effectively blocked by BI-1206. BI-1206 significantly enhanced the in vivo anti-MCL efficacy of rituximab-ibrutinib (p = 0.05) and rituximab-venetoclax (p = 0.02), but not the rituximab-CHOP combination in JeKo-1 cell line-derived xenograft models. In patient-derived xenograft (PDX) models, BI-1206, as a single agent, showed high potency (p < 0.0001, compared to vehicle control) in one aggressive PDX model that is resistant to both ibrutinib and venetoclax but sensitive to the combination of rituximab and lenalidomide (the preclinical mimetic of R(2) therapy). BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p = 0.030). Moreover, BI-1206 significantly enhanced the efficacy of the rituximab-venetoclax combination (p < 0.05), which led to long-term tumor remission in 25% of mice. Altogether, these data support that targeting this new immune-checkpoint blockade enhances the therapeutic activity of rituximab-based regimens in aggressive MCL models with multi-resistance. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13045-022-01257-9. BioMed Central 2022-04-11 /pmc/articles/PMC8996600/ /pubmed/35410313 http://dx.doi.org/10.1186/s13045-022-01257-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Letter to the Editor
Jiang, Vivian Changying
Liu, Yang
Jordan, Alexa
Leeming, Angela
McIntosh, Joseph
Huang, Shengjian
Zhang, Rongjia
Cai, Qingsong
Chen, Zhihong
Li, Yijing
Che, Yuxuan
Nie, Lei
Karlsson, Ingrid
Mårtensson, Linda
Kovacek, Mathilda
Teige, Ingrid
Frendéus, Björn
Wang, Michael
Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title_full Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title_fullStr Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title_full_unstemmed Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title_short Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
title_sort targeting fcγriib by antagonistic antibody bi-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma
topic Letter to the Editor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8996600/
https://www.ncbi.nlm.nih.gov/pubmed/35410313
http://dx.doi.org/10.1186/s13045-022-01257-9
work_keys_str_mv AT jiangvivianchangying targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT liuyang targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT jordanalexa targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT leemingangela targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT mcintoshjoseph targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT huangshengjian targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT zhangrongjia targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT caiqingsong targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT chenzhihong targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT liyijing targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT cheyuxuan targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT nielei targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT karlssoningrid targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT martenssonlinda targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT kovacekmathilda targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT teigeingrid targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT frendeusbjorn targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma
AT wangmichael targetingfcgriibbyantagonisticantibodybi1206improvestheefficacyofrituximabbasedtherapiesinaggressivemantlecelllymphoma