Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma
Abstract Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy,...
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| Format: | Article |
| Language: | English |
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BMC
2021-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-021-01184-9 |
| _version_ | 1831629661179740160 |
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| author | Xiaolei Lian Dina Kats Samuel Rasmussen Leah R. Martin Anju Karki Charles Keller Noah E. Berlow |
| author_facet | Xiaolei Lian Dina Kats Samuel Rasmussen Leah R. Martin Anju Karki Charles Keller Noah E. Berlow |
| author_sort | Xiaolei Lian |
| collection | DOAJ |
| description | Abstract Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG. |
| first_indexed | 2024-12-19T02:04:18Z |
| format | Article |
| id | doaj.art-26cfaf7f458f4996ac8ece720aa85a1a |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-19T02:04:18Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-26cfaf7f458f4996ac8ece720aa85a1a2022-12-21T20:40:58ZengBMCActa Neuropathologica Communications2051-59602021-05-019111210.1186/s40478-021-01184-9Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine gliomaXiaolei Lian0Dina Kats1Samuel Rasmussen2Leah R. Martin3Anju Karki4Charles Keller5Noah E. Berlow6Children’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteChildren’s Cancer Therapy Development InstituteAbstract Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.https://doi.org/10.1186/s40478-021-01184-9Diffuse intrinsic pontine gliomaAntibody–drug conjugatesImmunotherapyIL13Rα2Pediatric cancer |
| spellingShingle | Xiaolei Lian Dina Kats Samuel Rasmussen Leah R. Martin Anju Karki Charles Keller Noah E. Berlow Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma Acta Neuropathologica Communications Diffuse intrinsic pontine glioma Antibody–drug conjugates Immunotherapy IL13Rα2 Pediatric cancer |
| title | Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma |
| title_full | Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma |
| title_fullStr | Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma |
| title_full_unstemmed | Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma |
| title_short | Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma |
| title_sort | design considerations of an il13rα2 antibody drug conjugate for diffuse intrinsic pontine glioma |
| topic | Diffuse intrinsic pontine glioma Antibody–drug conjugates Immunotherapy IL13Rα2 Pediatric cancer |
| url | https://doi.org/10.1186/s40478-021-01184-9 |
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