All Publications

  • Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient. Advanced therapeutics Klich, J. H., Kasse, C. M., Mann, J. L., Huang, Y., d'Aquino, A. I., Grosskopf, A. K., Baillet, J., Fuller, G. G., Appel, E. A. 2023; 6 (1)


    Monoclonal antibodies are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Moreover, existing excipients designed to stabilize these formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, we demonstrate the ability of a simple "drop-in", amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically-relevant monoclonal antibodies without altering their pharmacokinetics or injectability. Through interfacial rheology and surface tension measurements, we demonstrate that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity through stressed aging, we show that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, we demonstrate that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as a simple formulation additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route-of-administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.

    View details for DOI 10.1002/adtp.202200102

    View details for PubMedID 36684707

    View details for PubMedCentralID PMC9854243

  • Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Correa, S., Meany, E. L., Gale, E. C., Klich, J. H., Saouaf, O. M., Mayer, A. T., Xiao, Z., Liong, C. S., Brown, R. A., Maikawa, C. L., Grosskopf, A. K., Mann, J. L., Idoyaga, J., Appel, E. A. 2022: e2103677


    When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or 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, this study explored the ability of a slow-releasing injectable hydrogel depot to reduce dose-limiting toxicities of immunostimulatory CD40agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer-nanoparticle (PNP) hydrogel system is leveraged that exhibits shear-thinning and yield-stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel-based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a-loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10melanoma model. PNP hydrogels, therefore, represent a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.

    View details for DOI 10.1002/advs.202103677

    View details for PubMedID 35975424

  • Yield-Stress and Creep Control Depot Formation and Persistence of Injectable Hydrogels Following Subcutaneous Administration ADVANCED FUNCTIONAL MATERIALS Jons, C. K., Grosskopf, A. K., Baillet, J., Yan, J., Klich, J. H., Saouaf, O. M., Appel, E. A. 2022
  • Injectable liposome-based supramolecular hydrogels for the programmable release of multiple protein drugs MATTER Correa, S., Grosskopf, A. K., Klich, J. H., Hernandez, H., Appel, E. A. 2022; 5 (6)
  • Injectable Liposome-based Supramolecular Hydrogels for the Programmable Release of Multiple Protein Drugs. Matter Correa, S., Grosskopf, A. K., Klich, J. H., Hernandez, H. L., Appel, E. A. 2022; 5 (6): 1816-1838


    Directing biological functions is at the heart of next-generation biomedical initiatives in tissue and immuno-engineering. However, the ambitious goal of engineering complex biological networks requires the ability to precisely perturb specific signaling pathways at distinct times and places. Using lipid nanotechnology and the principles of supramolecular self-assembly, we developed an injectable liposomal nanocomposite hydrogel platform to precisely control the release of multiple protein drugs. By integrating modular lipid nanotechnology into a hydrogel, we introduced multiple mechanisms of release based on liposome surface chemistry. To validate the utility of this system for multi-protein delivery, we demonstrated synchronized, sustained, and localized release of IgG antibody and IL-12 cytokine in vivo, despite the significant size differences between these two proteins. Overall, liposomal hydrogels are a highly modular platform technology with the ability the mediate orthogonal modes of protein release and the potential to precisely coordinate biological cues both in vitro and in vivo.

    View details for DOI 10.1016/j.matt.2022.03.001

    View details for PubMedID 35800848

    View details for PubMedCentralID PMC9255852

  • Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Science advances Grosskopf, A. K., Labanieh, L., Klysz, D. D., Roth, G. A., Xu, P., Adebowale, O., Gale, E. C., Jons, C. K., Klich, J. H., Yan, J., Maikawa, C. L., Correa, S., Ou, B. S., d'Aquino, A. I., Cochran, J. R., Chaudhuri, O., Mackall, C. L., Appel, E. A. 2022; 8 (14): eabn8264


    Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

    View details for DOI 10.1126/sciadv.abn8264

    View details for PubMedID 35394838