Multidomain peptide hydrogel adjuvants elicit strong bias towards humoral immunity

Pogostin, Brett H; Yu, Marina H; Azares, Alon R.; Euliano, Erin M.; Lai, Cheuk Sun Edwin; Saenz, Gabriel; Wu, Samuel S.; Farsheed, Adam C; Melhorn, Sarah; Graf, Tyler; Woodside, Darren G.; Hartgerink, Jeffrey D.; McHugh, Kevin J.

doi:10.1039/d2bm01242a

Cited by 12 publications

(20 citation statements)

References 61 publications

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“…Hydrogels were then plated (50 μL) into a custom 3D-printed 48-well plate in a depression on the left side of each well with a truncated pipet tip. The wells of the custom 48-well plate are printed on a Form 3+ 3D printer using PU Rigid 650 resin (Formlabs, Somerville, MA) by converting two laterally adjacent wells on a 96-well plate into a single oblong well with the same positions, so they are compatible with a microplate reader . The hydrogels were then plated on the left side of the well and then allowed to rest for 5 min to reform as hydrogels before supernatant (400 μL) was then added to each well (Figure S6).…”

Section: Methodsmentioning

confidence: 99%

“…K 2 was first designed in 2009, 41 and it has become one of the most widely studied MDPs for small molecule and protein delivery. 43,46,48 We hypothesized that the aldehydes on O-Man would react with the primary amines on the four lysine side chains of K 2 , forming reversible covalent imine bonds that would slow the release of O-Man but not R-Man, which lacks aldehyde groups (Figure 1). Dynamic imine bonds have been previously exploited for the controlled release of therapeutic payloads from biomaterials, bioconjugation of carbohydrates to proteins and peptides, and the development of shear-thinning carbohydrate-based hydrogels.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Composite delivery systems are of particular interest for combination cancer immunotherapy where several immunomodulatory agents delivered together can synergize to enhance treatment efficacy, and MDP hydrogels have been shown to have broad utility for the delivery of many therapeutic payloads. For example, previous investigations have used MDPs to modulate the delivery of proteins, small molecules, and liposomes in vitro and in vivo . ,− The ability of MDP hydrogels to control the release of carbohydrate payloads, however, has not been explored. MDPs have typically leveraged complementary electrostatic interactions or hydrophobic interactions to control the payload release rate.…”

Section: Introductionmentioning

confidence: 99%

“…These hydrogels are of particular interest due to their biocompatibility, shear recovery, and drug delivery capabilities . Their possible immunotherapy applications are bolstered by their modular amino acid building blocks, which allow for diverse chemical functionality that has been shown to influence host immune responses, including the preferential induction of humoral immunity . Composite delivery systems are of particular interest for combination cancer immunotherapy where several immunomodulatory agents delivered together can synergize to enhance treatment efficacy, and MDP hydrogels have been shown to have broad utility for the delivery of many therapeutic payloads.…”

Section: Introductionmentioning

confidence: 99%

“…In the current study, we investigated the ability of a lysine-rich MDP hydrogel, Ac–K 2 (SL) 6 K 2 –Am (referred to as K 2 ), to control the release of oxidized and reduced mannan in vitro and in vivo . K 2 was first designed in 2009, and it has become one of the most widely studied MDPs for small molecule and protein delivery. ,, We hypothesized that the aldehydes on O-Man would react with the primary amines on the four lysine side chains of K 2 , forming reversible covalent imine bonds that would slow the release of O-Man but not R-Man, which lacks aldehyde groups (Figure ). Dynamic imine bonds have been previously exploited for the controlled release of therapeutic payloads from biomaterials, bioconjugation of carbohydrates to proteins and peptides, and the development of shear-thinning carbohydrate-based hydrogels. − By leveraging this imine interaction, we found that K 2 significantly extends the release of oxidized mannan relative to reduced mannan in vitro and can prolong the release of O-Man but not R-Manwhich lacks the ability to form dynamic imine bonds in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

et al. 2022

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Recently, there has been increased interest in using mannan as an immunomodulatory bioconjugate. Despite notable immunological and functional differences between the reduced (R-Man) and oxidized (O-Man) forms of mannan, little is known about the impact of mannan oxidation state on its in vivo persistence or its potential controlled release from biomaterials that may improve immunotherapeutic or prophylactic efficacy. Here, we investigate the impact of oxidation state on the in vitro and in vivo release of mannan from a biocompatible and immunostimulatory multidomain peptide hydrogel, K 2 (SL) 6 K 2 (abbreviated as K 2 ), that has been previously used for the controlled release of protein and small molecule payloads. We observed that O-Man released more slowly from K 2 hydrogels in vitro than R-Man. In vivo, the clearance of O-Man from K 2 hydrogels was slower than O-Man alone. We attributed the slower release rate to the formation of dynamic imine bonds between reactive aldehyde groups on O-Man and the lysine residues on K 2 . This imine interaction was also observed to improve K 2 + O-Man hydrogel strength and shear recovery without significantly influencing secondary structure or peptide nanofiber formation. There were no observed differences in the in vivo release rates of O-Man loaded in K 2 , R-Man loaded in K 2 , and R-Man alone. These data suggest that, after subcutaneous injection, R-Man naturally persists longer in vivo than O-Man and minimally interacts with the peptide hydrogel. These results highlight a potentially critical, but previously unreported, difference in the in vivo behavior of O-Man and R-Man and demonstrate that K 2 can be used to normalize the release of O-Man to that of R-Man. Further, since K 2 itself is an adjuvant, a combination of O-Man and K 2 could be used to enhance the immunostimulatory effects of O-Man for applications such as infectious disease vaccines and cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

et al. 2022

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Peptide Hydrogels as Immunomaterials and Their Use in Cancer Immunotherapy Delivery

Falcone,

Ermis,

Tamay

et al. 2023

Adv Healthcare Materials

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Peptide‐based hydrogel biomaterials have emerged as an excellent strategy for immune system modulation. Peptide‐based hydrogels are supramolecular materials that self‐assemble into various nanostructures through various interactive forces (i.e., hydrogen bonding and hydrophobic interactions) and respond to microenvironmental stimuli (i.e., pH, temperature). While they have been reported in numerous biomedical applications, they have recently been deemed promising candidates to improve the efficacy of cancer immunotherapies and treatments. Immunotherapies seek to harness the body's immune system to preemptively protect against and treat various diseases, such as cancer. However, their low efficacy rates result in limited patient responses to treatment. Here, the immunomaterial's potential to improve these efficacy rates by either functioning as immune stimulators through direct immune system interactions and/or delivering a range of immune agents is highlighted. The chemical and physical properties of these peptide‐based materials that lead to immuno modulation and how one may design a system to achieve desired immune responses in a controllable manner are discussed. Works in the literature that reports peptide hydrogels as adjuvant systems and for the delivery of immunotherapies are highlighted. Finally, the future trends and possible developments based on peptide hydrogels for cancer immunotherapy applications are discussed.

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A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant

Euliano,

Pogostin,

Agrawal

et al. 2024

Adv Healthcare Materials

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Toll‐like receptors (TLRs) recognize pathogen‐ and damage‐associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants. Many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co‐localization with antigens and, thus, their effect. Here, the small‐molecule TLR7 agonist 1V209 is conjugated to a positively‐charged multidomain peptide (MDP) hydrogel, K2, which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209‐conjugated K2 50:50 with the unfunctionalized K2 produces hydrogels that retain the shear‐thinning and self‐healing physical properties of the original MDP while improving the solubility of 1V209 more than 200‐fold compared to the unconjugated molecule. When co‐delivered with ovalbumin as a model antigen, 1V209‐functionalized K2 produces a robust Th2 immune response and an antigen‐specific Th1 immune response superior to alum, a widely used vaccine adjuvant. Together, these results suggest that K2 MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response.

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Multidomain peptide hydrogel adjuvants elicit strong bias towards humoral immunity

Abstract: Adjuvants play a critical role in enhancing vaccine efficacy; however, there is a need to develop new immunomodulatory compounds to address emerging pathogens and to expand the use of immunotherapies....

Cited by 12 publications

References 61 publications

Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

Dynamic Imine Bonding Facilitates Mannan Release from a Nanofibrous Peptide Hydrogel

Peptide Hydrogels as Immunomaterials and Their Use in Cancer Immunotherapy Delivery

A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant

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