ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile

Autor: Hong I. Wan, Emma Sangalang, Tracy C. Kuo, Ons Harrabi, Laura Doyle, Janet Sim, Jaume Pons, Bora Han, Amy Y. Chen, Sangeetha Bollini, Sony S. Rocha, Steven E. Kauder
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Physiology
Cancer Treatment
Drug Evaluation
Preclinical
lcsh:Medicine
Adaptive Immunity
White Blood Cells
Mice
0302 clinical medicine
Antineoplastic Agents
Immunological
Animal Cells
Immune Physiology
Neoplasms
Medicine and Health Sciences
lcsh:Science
Immune Response
Multidisciplinary
Chemistry
T Cells
Acquired immune system
Cell biology
medicine.anatomical_structure
Oncology
Cell Processes
030220 oncology & carcinogenesis
Female
Cellular Types
Research Article
Cell Binding
Primates
Cell Physiology
T cell
Immune Cells
Immunology
Cytotoxic T cells
CD47 Antigen
Cell Line
03 medical and health sciences
Immune system
Phagocytosis
medicine
Animals
Humans
Tumor microenvironment
Innate immune system
Blood Cells
CD47
Macrophages
lcsh:R
Biology and Life Sciences
Dendritic cell
Cell Biology
Dendritic Cells
Immune checkpoint
Immunity
Innate
Immunoglobulin Fc Fragments
Rats
Macaca fascicularis
030104 developmental biology
lcsh:Q
Spleen
Neoplasm Transplantation
Zdroj: PLoS ONE, Vol 13, Iss 8, p e0201832 (2018)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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