Biology subjects

Fell, C.

Publications and source records attributed to Fell, C..

5 recordsLinked to original sources

bioRxiv2026

Once yearly cell-based therapy for sustained and dose tunable delivery of monoclonal antibodies

Over 200 monoclonal antibodies (mAbs) are approved for clinical use, yet their therapeutic potential is constrained by dependence on repeated injections or infusions that drive non-adherence, limit access in low-resource settings, and generate peak-trough pharmacokinetics linked to adverse effects and reduced efficacy. Here, we developed an immunomodulatory encapsulated cell-based biologics factory that overcomes mAb instability, immunogenicity, and the fibrotic foreign body response that have limited previous approaches, enabling continuous in situ production of therapeutic antibodies from a single administration. Screening chemically modified alginate biomaterials in immunocompetent mice identified a lead immunomodulatory alginate formulation that sustains stable serum titers of the HIV-neutralizing mAb 3BNC117 for one year. Single-cell RNA sequencing revealed that this formulation promotes a local anti-inflammatory, pro-resolving immune niche that attenuates fibrosis. The platforms versatility was demonstrated by production of thirteen diverse mAbs from an allogeneic cell chassis, with sustained in vivo delivery of a subset including ipilimumab, pembrolizumab, adalimumab, and PGT121. Integration into a retrievable macrodevice enabled on-demand therapeutic termination and re-implantation for dose-proportional tuning. In a non-human primates, subcutaneous implantation maintained stable ipilimumab titers for over six months with no detectable toxicity, anti-drug antibodies, or adverse events, and dose-dependent exposure was confirmed across a three-dose escalation. These results demonstrate a clinically translatable platform offering a practical strategy to replace frequent injections with single-administration therapy.

bioengineering↗

bioRxiv2026

Programmable Lipid Nanoparticle Targeting via Corona Engineering

Lipid nanoparticles (LNPs) are a versatile platform for in vivo delivery of biomolecules, yet systemically administered LNPs predominantly accumulate in the liver, limiting extrahepatic applications. This tropism arises from LNP adsorption of serum proteins, particularly apolipoprotein E (ApoE), which binds to LDL receptors (LDLR) on hepatocytes. Here, we overcome this tropism with two compatible strategies. First, we engineer dead ApoE mutants (dApoE) with five receptor-binding domain substitutions that selectively disrupt the ApoE-LDLR interaction but retain lipid binding. In cultured cells, pre-coating with these dApoE markedly inhibited LDLR-mediated uptake. Second, we pretreat cells with hyperactive PCSK9 (haPCSK9) to internalize surface LDLR, similarly reducing the LDLR-mediate uptake of LNPs. In vivo, both strategies substantially reduced liver LNP transduction without inducing redistribution to other major organs. To retarget LNP to new cell types we combined antibody conjugation with dApoE or haPCSK9, effectively engineering tropism to T cells, brain and lung tissues in vivo with substantially reduced hepatic background. In pilot studies, this strategy enabled specific delivery of reporter mRNAs to additional tissues, including megakaryocytes, hematopoietic progenitor cells, and cardiac tissue, and in aged T cells, to deliver miRNA cargos that produced a sustained reduction in DNA damage markers following a single systemic dose. dApoE coated CD5-targeted LNPs generated CAR+ T cells that retained cytotoxicity against CD19+ targets, while simultaneously reducing hepatocyte transduction by 90%. These findings establish a modular framework that integrates dApoE and haPCSK9-mediated detargeting with antibody-based retargeting, allowing for improvements in LNP specificity and broadening the therapeutic scope of LNPs.

bioengineering↗

bioRxiv2025

Factors Influencing Monoclonal Antibody Pharmacokinetics Across Varying Immune Perturbations

The development of continuous-release devices or injectables for the long-term delivery of biologics is of great interest, especially monoclonal antibodies (mAbs) that require frequent, high-dose injections. Preclinical testing of these technologies in murine models is necessary for clinical translation; however, xenogeneic responses to the mAb and foreign body responses to the implants or injectables can confound results. Immune system knockout (KO) models that affect immune cells are often used in these experiments, but the effects of KO models on mAb pharmacokinetics (PK) are not well characterized. Here, we investigated the PK profile of the human mAb 3BNC117 after intravenous, subcutaneous, and intraperitoneal injections in four mouse strains: BL6, BCD, RAG2, and NSG mice. Noncompartmental analysis was used to quantify differences in PK between each mouse strain. Strikingly, both BL6 and NSG mice exhibited significantly higher mAb clearance compared to the other two strains. To better understand these differences, we developed a minimally physiological based PK model of mAb PK and estimated model parameters using nonlinear mixed effects modeling. The fitted model parameters illustrated how specific processes change in each strain, including the change in clearance rates over time in BL6 and differences in mAb lymphatic uptake in NSG mice. We then used simple allometric scaling relationships to assess which strains were reasonably predictive of human mAb PK. NSG and BL6 mice were found to be unpredictive of human PK, unlike RAG2 and BCD mice. Overall, these results highlight the importance of selecting an appropriate KO strain for preclinical mAb evaluation and demonstrate that RAG2 and BCD strains are suitable mouse models for investigation of mAb PK. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/651349v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@138af32org.highwire.dtl.DTLVardef@763196org.highwire.dtl.DTLVardef@1b17331org.highwire.dtl.DTLVardef@10199e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Electrocatalytic on-site oxygenation for transplanted cell-based-therapies

Implantable cell therapies and tissue transplants require sufficient oxygen supply to function and are limited by a delay or lack of vascularization from the transplant host1, 2. Exogenous oxygen production can support cells and tissues, such as pancreatic islets and engineered therapeutic cells. Previous oxygenation strategies have targeted gas circulation or decomposition of solid peroxides. These strategies however require bulky implants, transcutaneous supply lines, and are limited in their total oxygen production or regulation3, 4. Readily integrated and controlled production of oxygen has eluded cell therapy devices. Here, we show an electrocatalytic approach that enables bioelectronic control of oxygen generation in complex cellular environments to sustain engineered cell viability and therapy production under hypoxic stress and at high cell densities. Nanostructured sputtered iridium oxide serves as an ideal catalyst for oxygen evolution reaction (OER) at neutral pH. It enables a lower OER onset and shows selective oxygen production without evolution of toxic side products over a 300 mV window of operation. This electrocatalytic on site oxygenator (ecO2) can sustain high cell loadings (>60k cells/mm3) in hypoxic conditions in vitro and in vivo. Our results demonstrate that exogenous oxygen production devices can be readily integrated into bioelectronic platforms and enable high cell loadings in smaller device footprints with broad applicability.

bioengineering↗

bioRxiv2021

Bio-hybrid Soft Robotic Bioreactors for Mimicking Multi-Axial Femoropopliteal Artery Mechanobiology

The emerging field of soft robotics aims to emulate dynamic physiological locomotion. Soft robotics mimicry of naturally complex biomechanics makes them ideal platforms for exerting mechanical stimuli for patient-specific tissue maturation and disease modeling applications. Such platforms are essential for emulating highly flexible tissues such as the kneecaps femoropopliteal artery (FPA), one of the most flexible arteries in the body, which flexes and bends during walking, standing, and crouching movements. The FPA is a frequent site of disease, where 80% of all peripheral artery diseases manifest, affecting over 200 million people worldwide. The complex biomechanical and hemodynamic forces within the FPA have been implicated in the frequent occurrence of PAD and lead to debilitating morbidities, such as limb-threatening ischemia. To better mimic these complex biomechanics, we developed an in-vitro bio-hybrid soft robot (BSR). First, Platsil OO-20 was identified as an ideal hyperelastomer for both cell culture and BSR fabrication using 3D printed molds. Then, employing a simulation-based design workflow, we integrated pneumatic network (PneuNet) actuators cast with Platsil OO-20, which extend in angular, longitudinal, and radial dimensions. Pressurizing the BSR PneuNets enabled a range of mechanical stimuli to be dynamically applied during tissue culture to mimic normal and diseased FPA flexions during daily walking and sitting poses, the most extreme being radial distensions of 20% and angular flexions of 140{degrees}. Finally, these designed, manufactured, and programmed vascular BSRs were seeded with mesenchymal stem cells and conditioned for 24 hours to highlight the effect of dynamic conditioning on cultured cell alignment, as well as type IV collagen production and the upregulation of smooth muscle phenotypes. Soft robotic bioreactor platforms that accurately mimic patient-, disease-, and lifestyle-specific mechanobiology will develop fundamental disease understanding, preoperative laboratory simulations for existing therapeutics, and biomanufacturing platforms for tissue-engineered implants.

bioengineering↗