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T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia
BACKGROUND: Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies targe...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154967/ https://www.ncbi.nlm.nih.gov/pubmed/34035113 http://dx.doi.org/10.1136/jitc-2021-002509 |
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author | Hoseini, Sayed Shahabuddin Vadlamudi, Mallika Espinosa-Cotton, Madelyn Tran, Hoa Feng, Yi Guo, Hong-fen Xu, Hong Cheung, Irene Cheung, Nai-Kong V |
author_facet | Hoseini, Sayed Shahabuddin Vadlamudi, Mallika Espinosa-Cotton, Madelyn Tran, Hoa Feng, Yi Guo, Hong-fen Xu, Hong Cheung, Irene Cheung, Nai-Kong V |
author_sort | Hoseini, Sayed Shahabuddin |
collection | PubMed |
description | BACKGROUND: Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies target the membrane distal immunoglobulin V (IgV) domain of the CD33 extracellular domain. METHODS: In this manuscript, we present data on three bispecific antibodies (BsAbs) against the CD33 IgV and membrane proximal immunoglobulin C (IgC) domains. We use in vitro binding and cytotoxicity assays to show the effect of these BsAbs on AML cell lines. We also use immunodeficient mice-bearing leukemias from cell lines and patient-derived xenografts to show the effect of these BsAbs in vivo. RESULTS: In vitro, the IgV-targeting BsAb had higher binding to AML cell lines using flow cytometry and delivered more potent cytotoxicity in T-cell-dependent cytotoxicity assays; importantly, the IgC domain-targeting outperformed the IgV domain-targeting BsAb in medullary and extramedullary leukemia animal models. CONCLUSIONS: These data support further clinical development of this BsAb for first-in-human phase I clinical trial. |
format | Online Article Text |
id | pubmed-8154967 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-81549672021-06-10 T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia Hoseini, Sayed Shahabuddin Vadlamudi, Mallika Espinosa-Cotton, Madelyn Tran, Hoa Feng, Yi Guo, Hong-fen Xu, Hong Cheung, Irene Cheung, Nai-Kong V J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Acute myeloid leukemia (AML) remains one of the most challenging hematological malignancies. Despite progress in therapeutics, majority of patients succumb to this neoplasm. CD33 is a proven therapeutic target, given its expression on most AML cells. Almost all anti-CD33 antibodies target the membrane distal immunoglobulin V (IgV) domain of the CD33 extracellular domain. METHODS: In this manuscript, we present data on three bispecific antibodies (BsAbs) against the CD33 IgV and membrane proximal immunoglobulin C (IgC) domains. We use in vitro binding and cytotoxicity assays to show the effect of these BsAbs on AML cell lines. We also use immunodeficient mice-bearing leukemias from cell lines and patient-derived xenografts to show the effect of these BsAbs in vivo. RESULTS: In vitro, the IgV-targeting BsAb had higher binding to AML cell lines using flow cytometry and delivered more potent cytotoxicity in T-cell-dependent cytotoxicity assays; importantly, the IgC domain-targeting outperformed the IgV domain-targeting BsAb in medullary and extramedullary leukemia animal models. CONCLUSIONS: These data support further clinical development of this BsAb for first-in-human phase I clinical trial. BMJ Publishing Group 2021-05-25 /pmc/articles/PMC8154967/ /pubmed/34035113 http://dx.doi.org/10.1136/jitc-2021-002509 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Hoseini, Sayed Shahabuddin Vadlamudi, Mallika Espinosa-Cotton, Madelyn Tran, Hoa Feng, Yi Guo, Hong-fen Xu, Hong Cheung, Irene Cheung, Nai-Kong V T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title | T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title_full | T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title_fullStr | T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title_full_unstemmed | T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title_short | T cell engaging bispecific antibodies targeting CD33 IgV and IgC domains for the treatment of acute myeloid leukemia |
title_sort | t cell engaging bispecific antibodies targeting cd33 igv and igc domains for the treatment of acute myeloid leukemia |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154967/ https://www.ncbi.nlm.nih.gov/pubmed/34035113 http://dx.doi.org/10.1136/jitc-2021-002509 |
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