Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies

Abstract

When properly deployed, the immune system can render deadly pathogens harmless, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. However, realizing these remarkable capabilities is inherently risky, as disruption to immune homeostasis can lead to dangerous complications and autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, we explored the ability of a slow-releasing injectable hydrogel depot to reduce the problematic dose-limiting toxicities of immunostimulatory CD40 agonist antibodies (CD40a) while maintaining their potent anti-cancer efficacy. We previously described a polymer-nanoparticle (PNP) hydrogel system that is biocompatible, long lasting, and injectable, traits that we hypothesized would improve locoregional delivery of the CD40a immunotherapy. Using PET imaging, we found that hydrogels significantly improve CD40a pharmacokinetics by redistributing drug exposure to the tumor and the tumor draining lymph node (TdLN). Consistent with this altered biodistribution, hydrogel delivery significantly reduced weight loss, hepatotoxicity, and cytokine storm associated with treatment. Moreover, CD40a-loaded hydrogels were able to mediate improved local cytokine induction in the TdLN and improve treatment efficacy in both mono- and combination therapy settings in the B16F10 melanoma model. These results suggest that PNP hydrogels are a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.

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

“…More broadly, burst release is concerning for therapeutics that exhibit dose-dependent toxicity; while bnAbs are generally well-tolerated even in high doses, this material could also be used for other applications where toxicity is a concern, such as in cancer immunotherapy. 17,35…”

“…These PNP hydrogels have been shown to be injectable, biocompatible in vivo, and drug-stabilizing and have been shown to be effective for a range of biomedical applications including cell encapsulation and delivery, vaccine delivery, cancer immunotherapy, and adhesion prevention. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] In this work, we study the suitability of the PNP hydrogel platform to effectively deliver antibodies against SARS-CoV-2, and more broadly, we seek to investigate what is required to effectively design materials to act as a subcutaneous delivery depot for antibody therapeutics. We first evaluate the rheological characteristics, in vitro antibody release kinetics, and antibody stability in the PNP hydrogel system.…”

Injectable polymer-nanoparticle hydrogel for the sustained intravitreal delivery of bimatoprost

“…While these PNP hydrogels have been used for controlled delivery in various tissues (e.g., peritoneal cavity, thoracic cavity, and subcutaneous tissue) in multiple animal models (e.g., mice, rats, and sheep), this work is the first to pursue ITV administration in the sensitive environment of the eye. [13d, 13e, 16, 21] To better visualize and understand how the PNP hydrogels would behave in the VH of the eye, we first analyzed their depot formation and model cargo release in a VH mimic composed of agar and hyaluronic acid ( Figure 3 ). [22] For comparison, we evaluated the administration of PNP hydrogels containing either fluorescein (a model small molecule similar in size and hydrophobicity to bimatoprost) and albumin-FITC (a model protein) through a 30-gauge needle into a cuvette containing VH mimic.…”

Injectable liposome-based supramolecular hydrogels for the programmable release of multiple protein drugs

“…[9][10][11] In terms of scheduled multi-drug release, nanomedicine has been successful in staging the release of different classes of drugs (e.g., hydrophilic vs. hydrophobic small molecules, nucleic acids, proteins), but staged delivery of proteins remains a challenge. 8,12 Meanwhile, the emergence of injectable hydrogels has provided a significant improvement for minimally invasive localized therapy, [13][14][15][16][17][18][19][20][21][22] but scheduled multi-drug release from these systems is often limited to strategies that leverage sizegoverned (e.g., smaller drugs first) or solubility-governed (e.g., most soluble drugs first) release mechanisms. 7,23 Overall, there remains no minimally invasive delivery technology that can tune the relative release rates of multiple protein drugs in vivo.…”