Preclinical development of the TLR9 agonist DV281 as an inhaled aerosolized immunotherapeutic for lung cancer: Pharmacological profile in mice, non-human primates, and human primary cells.
Int Immunopharmacol
; 66: 296-308, 2019 Jan.
Article
en En
| MEDLINE
| ID: mdl-30502651
ABSTRACT
CpG-motif-containing oligodeoxynucleotides (CpG-ODN) activate innate immunity through Toll-Like Receptor (TLR) 9 signaling and generate local immune responses when delivered directly to the lung. Herein we describe pharmacological studies in mice, cynomolgus monkeys, and in human primary cells which support the development of DV281, a C-class CpG-ODN, as an inhaled aerosolized immunotherapeutic for lung cancer to be combined with an inhibitor of the anti-programmed cell death protein 1 (PD1) immune checkpoint. In vitro, DV281 potently induced Interferon (IFN)α from monkey and human peripheral blood mononuclear cells (PBMCs), stimulated interleukin6 production and proliferation in human B cells, and induced TLR9-dependent cytokine responses from mouse splenocytes. Intranasal delivery of DV281 to mice led to substantial but transient cytokine and chemokine responses in the lung. Lung responses to repeated intranasal DV281 were partially to fully reversible 2â¯weeks after the final dose and were absent in TLR9-deficient mice. Single escalating doses of aerosolized DV281 in monkeys induced dose-dependent induction of IFN-regulated genes in bronchoalveolar lavage cells and blood. In a repeat-dose safety study in monkeys, inhaled DV281 was well-tolerated, and findings were mechanism of action-related and non-adverse. Co-culture of human PBMC with DV281 and anti-PD1 antibody did not augment cytokine or cellular proliferation responses compared to DV281 alone, indicating that the combination did not lead to dysregulated cytokine responses. These studies support clinical development of inhaled aerosolized DV281 as a combination therapy with anti-PD1 antibody for lung cancer immunotherapy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oligodesoxirribonucleótidos
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Linfocitos B
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Protocolos de Quimioterapia Combinada Antineoplásica
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Receptor Toll-Like 9
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Inmunoterapia
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Neoplasias Pulmonares
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Anticuerpos Monoclonales
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Int Immunopharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos