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ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile
CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer. When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104973/ https://www.ncbi.nlm.nih.gov/pubmed/30133535 http://dx.doi.org/10.1371/journal.pone.0201832 |
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author | Kauder, Steven E. Kuo, Tracy C. Harrabi, Ons Chen, Amy Sangalang, Emma Doyle, Laura Rocha, Sony S. Bollini, Sangeetha Han, Bora Sim, Janet Pons, Jaume Wan, Hong I. |
author_facet | Kauder, Steven E. Kuo, Tracy C. Harrabi, Ons Chen, Amy Sangalang, Emma Doyle, Laura Rocha, Sony S. Bollini, Sangeetha Han, Bora Sim, Janet Pons, Jaume Wan, Hong I. |
author_sort | Kauder, Steven E. |
collection | PubMed |
description | CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer. When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in the suppression of adaptive antitumor responses, but the relevant cellular functions have yet to be elucidated. Therapeutic blockade of the CD47 pathway may stimulate antitumor immunity and improve cancer therapy. To this end, a novel CD47-blocking molecule, ALX148, was generated by fusing a modified SIRPα D1 domain to an inactive human IgG1 Fc. ALX148 binds CD47 from multiple species with high affinity, inhibits wild type SIRPα binding, and enhances phagocytosis of tumor cells by macrophages. ALX148 has no effect on normal human blood cells in vitro or on blood cell parameters in rodent and non-human primate studies. Across several murine tumor xenograft models, ALX148 enhanced the antitumor activity of different targeted antitumor antibodies. Additionally, ALX148 enhanced the antitumor activity of multiple immunotherapeutic antibodies in syngeneic tumor models. These studies revealed that CD47 blockade with ALX148 induces multiple responses that bridge innate and adaptive immunity. ALX148 stimulates antitumor properties of innate immune cells by promoting dendritic cell activation, macrophage phagocytosis, and a shift of tumor-associated macrophages toward an inflammatory phenotype. ALX148 also stimulated the antitumor properties of adaptive immune cells, causing increased T cell effector function, pro-inflammatory cytokine production, and a reduction in the number of suppressive cells within the tumor microenvironment. Taken together, these results show that ALX148 binds and blocks CD47 with high affinity, induces a broad antitumor immune response, and has a favorable safety profile. |
format | Online Article Text |
id | pubmed-6104973 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61049732018-09-15 ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile Kauder, Steven E. Kuo, Tracy C. Harrabi, Ons Chen, Amy Sangalang, Emma Doyle, Laura Rocha, Sony S. Bollini, Sangeetha Han, Bora Sim, Janet Pons, Jaume Wan, Hong I. PLoS One Research Article CD47 is a widely expressed cell surface protein that functions as an immune checkpoint in cancer. When expressed by tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. CD47-SIRPα signaling has also been implicated in the suppression of adaptive antitumor responses, but the relevant cellular functions have yet to be elucidated. Therapeutic blockade of the CD47 pathway may stimulate antitumor immunity and improve cancer therapy. To this end, a novel CD47-blocking molecule, ALX148, was generated by fusing a modified SIRPα D1 domain to an inactive human IgG1 Fc. ALX148 binds CD47 from multiple species with high affinity, inhibits wild type SIRPα binding, and enhances phagocytosis of tumor cells by macrophages. ALX148 has no effect on normal human blood cells in vitro or on blood cell parameters in rodent and non-human primate studies. Across several murine tumor xenograft models, ALX148 enhanced the antitumor activity of different targeted antitumor antibodies. Additionally, ALX148 enhanced the antitumor activity of multiple immunotherapeutic antibodies in syngeneic tumor models. These studies revealed that CD47 blockade with ALX148 induces multiple responses that bridge innate and adaptive immunity. ALX148 stimulates antitumor properties of innate immune cells by promoting dendritic cell activation, macrophage phagocytosis, and a shift of tumor-associated macrophages toward an inflammatory phenotype. ALX148 also stimulated the antitumor properties of adaptive immune cells, causing increased T cell effector function, pro-inflammatory cytokine production, and a reduction in the number of suppressive cells within the tumor microenvironment. Taken together, these results show that ALX148 binds and blocks CD47 with high affinity, induces a broad antitumor immune response, and has a favorable safety profile. Public Library of Science 2018-08-22 /pmc/articles/PMC6104973/ /pubmed/30133535 http://dx.doi.org/10.1371/journal.pone.0201832 Text en © 2018 Kauder et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Kauder, Steven E. Kuo, Tracy C. Harrabi, Ons Chen, Amy Sangalang, Emma Doyle, Laura Rocha, Sony S. Bollini, Sangeetha Han, Bora Sim, Janet Pons, Jaume Wan, Hong I. ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title | ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title_full | ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title_fullStr | ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title_full_unstemmed | ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title_short | ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
title_sort | alx148 blocks cd47 and enhances innate and adaptive antitumor immunity with a favorable safety profile |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104973/ https://www.ncbi.nlm.nih.gov/pubmed/30133535 http://dx.doi.org/10.1371/journal.pone.0201832 |
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