Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot

Kasse, Catherine M.; Yu, Anthony C.; Chen, Alex; Roth, Gillie A.; Liong, Celine S.; Jons, Carolyn K.; Buahin, Awua; Maikawa, Caitlin L.; Zhou, Xin; Youssef, Sawsan; Glanville, Jacob; Appel, Eric A.

doi:10.1039/d2bm00819j

Cited by 19 publications

(14 citation statements)

References 75 publications

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“…PNP‐1‐5 was, therefore, selected as the formulation of choice for the next steps of the study. Importantly, like previous reports, [ 12,24 ] we did not observe foreign body responses or indications of poor tolerability of PNP hydrogels, demonstrating their excellent biocompatibility (Figures S4 and S5, Supporting Information).…”

Section: Resultssupporting

confidence: 89%

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS‐CoV‐2 Subunit Vaccine

Saouaf

Yan

et al. 2023

Adv Healthcare Materials

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Most vaccines require several immunizations to induce robust immunity, and indeed, most SARS‐CoV‐2 vaccines require an initial two‐shot regimen followed by several boosters to maintain efficacy. Such a complex series of immunizations unfortunately increases the cost and complexity of populations‐scale vaccination and reduces overall compliance and vaccination rate. In a rapidly evolving pandemic affected by the spread of immune‐escaping variants, there is an urgent need to develop vaccines capable of providing robust and durable immunity. In this work, a single immunization SARS‐CoV‐2 subunit vaccine is developed that can rapidly generate potent, broad, and durable humoral immunity. Injectable polymer–nanoparticle (PNP) hydrogels are leveraged as a depot technology for the sustained delivery of a nanoparticle antigen (RND‐NP) displaying multiple copies of the SARS‐CoV‐2 receptor‐binding domain (RBD) and potent adjuvants including CpG and 3M‐052. Compared to a clinically relevant prime‐boost regimen with soluble vaccines formulated with CpG/alum or 3M‐052/alum adjuvants, PNP hydrogel vaccines more rapidly generated higher, broader, and more durable antibody responses. Additionally, these single‐immunization hydrogel‐based vaccines elicit potent and consistent neutralizing responses. Overall, it is shown that PNP hydrogels elicit improved anti‐COVID immune responses with only a single administration, demonstrating their potential as critical technologies to enhance overall pandemic readiness.

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Section: Resultssupporting

confidence: 89%

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS‐CoV‐2 Subunit Vaccine

Saouaf

Yan

et al. 2023

Adv Healthcare Materials

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“…Based on all of the data described above, the L-0.9 mg 1-10 and 2-10 hydrogel formulations exhibited the most consistent and favorable pharmacokinetics, reaching steady state after just one day and maintaining stable and therapeutically relevant concentrations for the duration of the 42-day study. Yet, beyond evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of hydrogel-based GLP-1 RA therapies, simple pharmacokinetic modeling can be used to predict drug release kinetics in more clinically relevant large animals and in humans, while also aiding in the design of biomaterial depot technologies ( 41 ). Modeling can inform the optimization of the PNP hydrogel platform for delivery of cargo with similar physicochemical characteristics but different pharmacokinetic characteristics.…”

Section: Resultsmentioning

confidence: 99%

“…As the standard clinical dosing of semaglutide for type 2 diabetes is ~1 mg weekly, we anticipated that a single administration capable of providing upwards of four months of continuous therapy must contain ~20 mg of semaglutide in a volume relevant for subcutaneous administration (e.g., generally 0.5-2 mL). We have previously reported that these injectable, biocompatible PNP hydrogel materials are capable of facile loading of diverse protein cargo at relevant concentrations with high efficiency, and enable tunable cargo delivery timeframes (32,36,(39)(40)(41)(42)(43).…”

Section: Development Of Injectable Hydrogels For Sustained Release Of...mentioning

confidence: 99%

“…We therefore sought to leverage an injectable hydrogel platform generated through selfassembly of dynamic, entropically-driven supramolecular interactions between biodegradable nanoparticles (NPs) and hydrophobically-modified hydroxypropyl methylcellulose (HPMC) derivatives to develop a long-acting GLP-1 RA formulation (Figure 1E) (31)(32)(33)(34)(35)(36)(37)(38). We have previously shown these polymer-nanoparticle (PNP) hydrogels to be capable of providing application-specific release of diverse biopharmaceuticals such as proteins, vaccines, and cells that is tunable over timeframes extending from days to upwards of six months (32,36,(39)(40)(41)(42)(43).…”

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confidence: 99%

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Sustained Delivery of GLP-1 Receptor Agonists from Injectable Biomimetic Hydrogels Improves Treatment of Diabetes

d’Aquino

Maikawa

Nguyen

et al. 2023

Preprint

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone and neurotransmitter secreted from intestinal L-cells in response to nutrients to stimulate insulin and block glucagon secretion in a glucose-dependent manner. GLP-1 in itself is rapidly degraded, but long-acting GLP-1 receptor agonists (GLP-1 RAs) have become central in the treatment of T2D because of the beneficial effects extending also beyond glucose control. Currently, these therapeutics must be injected either daily or weekly or taken daily orally, leaving room for technological innovations that enable less frequent administrations, which will reduce patient burden and increase patient compliance. An ideal GLP-1 RA drug product would provide continuous therapy for upwards of four months from a single administration to match the cadence with which T2D patients typically visit their physician. In this work, we leveraged an injectable hydrogel depot technology to develop a long-acting GLP-1 RA drug product. By modulating the hydrogel properties to tune GLP-1 RA retention within the hydrogel depot, we engineered formulations capable of months-long GLP-1 RA delivery. Using a rat model of T2D, we confirmed that a single injection of hydrogel-based therapies exhibits sustained exposure of GLP-1 RA over 42 days, corresponding to a once-every four month therapy in humans. Moreover, these hydrogel therapies maintained optimal management of blood glucose and weight comparable to daily injections of a leading GLP-1 RA drug molecule. The pharmacokinetics and pharmacodynamics of these hydrogel-based long-acting GLP-1 RA treatments are promising for development of novel therapies reducing treatment burden for more effective management of T2D.

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“…Our lab has previously developed a self-assembled hydrogel platform for biomedical applications including sustained delivery of physicochemically diverse therapeutic cargo. [13][14][15][16][17][18][19][20] Our efforts have focused on the development of shear-thinning and selfhealing physical hydrogels that can be easily injected and which can afford sustained delivery of multifarious vaccine cargo. [13,[21][22][23][24] Specifically, these hydrogel materials leverage strong, non-covalent polymer-nanoparticle (PNP) interactions to crosslink biopolymer chains.…”

Section: Introductionmentioning

confidence: 99%

A regimen compression strategy for commercial vaccines leveraging an injectable hydrogel depot technology for sustained vaccine exposure

Yan

Saouaf

et al. 2023

Preprint

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Equitable global access to vaccines requires we overcome challenges associated with complex immunization schedules and their associated economic burdens that hinder delivery in under resourced environments. The rabies vaccine, for example, requires multiple immunizations for effective protection and each dose is cost prohibitive, and therefore inaccessibility disproportionately impacts low- and middle-income countries. In this work we developed an injectable hydrogel depot technology for sustained delivery of commercial inactivated rabies virus vaccines. In a mouse model, we showed that a single immunization of a hydrogel-based rabies vaccine elicited comparable antibody titers to a standard prime-boost bolus regimen of a commercial rabies vaccine, despite these hydrogel vaccines comprising only half of the total dose delivered in the bolus control. Moreover, these hydrogel-based vaccines elicited similar antigen-specific T-cell responses and neutralizing antibody responses compared to the bolus vaccine. Notably, we demonstrated that while addition of a potent clinical TLR4 agonist adjuvant to the gels slightly improved binding antibody responses, inclusion of this adjuvant to the inactivated virion vaccine was detrimental to neutralizing responses. Taken together, these results suggest that these hydrogels can enable an effective regimen compression and dose-sparing strategy for improving global access to vaccines.

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Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot

Abstract: Prolonged maintenance of therapeutically-relevant levels of broadly neutralizing antibodies (bnAbs) is necessary to enable passive immunization against infectious disease.

Cited by 19 publications

References 75 publications

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS‐CoV‐2 Subunit Vaccine

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS‐CoV‐2 Subunit Vaccine

Sustained Delivery of GLP-1 Receptor Agonists from Injectable Biomimetic Hydrogels Improves Treatment of Diabetes

A regimen compression strategy for commercial vaccines leveraging an injectable hydrogel depot technology for sustained vaccine exposure

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