Lipid conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01

Wilkinson, Alexander; Lattmann, Eric; Roces, Carla B.; Pedersen, Gabriel Kristian; Christensen, Dennis; Perrie, Yvonne

doi:10.1016/j.jconrel.2018.10.002

Cited by 21 publications

(17 citation statements)

References 64 publications

(78 reference statements)

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“…In addition, certain adjuvants are compounds with a low molecular weight (MW), and incorporation in liposomes or other VADSs can guarantee their co-delivery with Ags to the same population of APCs, while avoiding a systemic distribution and off-target cellular uptake. For example, resiquimod, a small water-soluble agonist of the endosome-located TLR7/8, will rapidly distribute throughout the body after injection in an aqueous solution and, when conjugated to cationic liposomes composed of DDA/TDB, has achieved co-delivery with Ags in mouse models, though this bound combination did not significantly elevate the already strong adjuvanticity of the cationic liposomes [127].…”

Section: Ag Release and Liposome Integrity In Vivomentioning

confidence: 99%

Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization

Wang

Chen

Wang

2019

Journal of Controlled Release

226

155

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Section: Ag Release and Liposome Integrity In Vivomentioning

confidence: 99%

Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization

Wang

Chen

Wang

2019

Journal of Controlled Release

226

155

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“…This effect was not restricted to the 3M-052 ligand as the adsorption of another TLR7/8 agonist compound to alum (28) potentiates immune responses to glycoconjugate (52) or pertussis vaccines (53). In contrast, Wilkinson et al recently reported that the lipid conjugation of the TLR7 agonist resiquimod to CAF01 does not potentiate immune responses, despite a depot at the site of immunization (54). However, CAF01 already induces strong T H 1 responses (55) and contains the potent TDB immunomodulator which promotes APC activation through the C-type lectin receptor Mincle (56).…”

Section: Discussionmentioning

confidence: 97%

A TLR7/8 Agonist-Including DOEPC-Based Cationic Liposome Formulation Mediates Its Adjuvanticity Through the Sustained Recruitment of Highly Activated Monocytes in a Type I IFN-Independent but NF-κB-Dependent Manner

et al. 2020

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Novel adjuvants, such as Toll-like receptors (TLRs) agonists, are needed for the development of new formulations able to circumvent limitations of current vaccines. Among TLRs, TLR7/8 agonists represent promising candidates, as they are well described to enhance antigen-specific antibody responses and skew immunity toward T helper (T H ) 1 responses. We find here that the incorporation of the synthetic TLR7/8 ligand 3M-052 in a cationic DOEPC-based liposome formulation shifts immunity toward T H 1 responses and elicits strong and long-lasting germinal center and follicular T helper cell responses in adult mice. This reflects the prolonged recruitment of innate cells toward the site of immunization and homing of activated antigen-loaded monocytes and monocyte-derived dendritic cells toward draining lymph nodes. We further show that this adjuvanticity is independent of type I IFN but NF-κB-dependent. Overall, our data identify TLR7/8 agonists incorporated in liposomes as promising and effective adjuvants to enhance T H 1 and germinal center responses.

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“…antigen IFN-g responses in the spleen can be 15 times higher whilst IL-17 is 6 times high [36]. There…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Formulation and manufacturing of lymphatic targeting liposomes using microfluidics

Khadke

Roces

Cameron

et al. 2019

Journal of Controlled Release

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The lymphatics are a target for a range of therapeutic purposes, including cancer therapy and vaccination and both vesicle size and charge have been considered as factors controlling lymphatic targeting. Within this work, a range of liposomal formulations were investigated to develop a liposomal lymphatic targeting system. Initial screening of formulations considered the effect of charge, with neutral, cationic and anionic liposomes being considered. Biodistribution studies demonstrated that after intramuscular injection, anionic liposomes offered the most rapid clearance to the draining lymphatics with cationic liposomes forming a depot at the injection site. Anionic liposomes containing phosphatidylserine showed higher clearance to the lymphatics and this may be a results of preferential uptake by macrophages. In terms of vesicle size, smaller unilamellar vesicles gave high lymphatic targeting and 10-fold increases in concentration were achieved in dose escalation studies (up to 40 mg of lipids). Given that effective trafficking to the lymphatics was achieved, the next step was to enhance retention of the liposomes within the lymphatics, therefore this liposome formulation was combined with an avidin/biotin complex mechanism. The affinity of avidin for biotin allows biotinylated liposomes to complex in the presence of avidin. By pre-dosing with avidin, this biotin-avidin complex can be exploited to promote longer retention of the liposomes at the draining lymphatics. To load these small, biotinylated liposomes with protein, microfluidics manufacturing was used. Using microfluidics, protein could easily be incorporated in these small (~90 nm) biotinylated liposomes. Both liposome and protein retention at the local draining lymph nodes was demonstrated with the liposome-biotin-avidin system. These results demonstrate that microfluidics can be used to prepare protein-loaded liposomes that offer enhanced lymphatic targeting and retention of both the liposomes and entrapped antigen.

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Lipid conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01

Abstract: conjugation of TLR7 agonist Resiquimod ensures co-delivery with the liposomal Cationic Adjuvant Formulation 01 (CAF01) but does not enhance immunopotentiation compared to non-conjugated Resiquimod+CAF01. Corel (2018),

Cited by 21 publications

References 64 publications

Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization

Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization

A TLR7/8 Agonist-Including DOEPC-Based Cationic Liposome Formulation Mediates Its Adjuvanticity Through the Sustained Recruitment of Highly Activated Monocytes in a Type I IFN-Independent but NF-κB-Dependent Manner

Formulation and manufacturing of lymphatic targeting liposomes using microfluidics

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