Biology subjects

Duhamel, L.

Publications and source records attributed to Duhamel, L..

2 recordsLinked to original sources

bioRxiv2026

Engineering hyaluronic acid-binding cytokines for enhanced tumor retention and safety

Intratumoral delivery of immunotherapy offers a means to enhance efficacy while limiting systemic toxicity, yet rapid diffusion from the tumor constrains dosing levels. Extracellular matrix-targeted anchoring strategies have emerged to improve tumor retention, but the influence of matrix target choice remains poorly understood. Here, we engineered a hyaluronic acid-anchoring platform and directly compared it to a well-established collagen-binding strategy for the delivery of IL-12/IL-15 combination therapy, assessing pharmacokinetic, efficacy, and toxicity endpoints. Hyaluronic acid anchoring markedly enhanced intratumoral retention and tumor loading relative to both unanchored and collagen-anchored constructs. While all anchored cytokine therapies achieved comparable curative tumor control, hyaluronic acid anchoring was associated with improved tolerability, including attenuated systemic inflammation, reduced liver toxicity, and diminished local tissue damage. Analysis of intratumoral immune signaling further indicated that the anchoring strategy modulates local cytokine exposure and immune cell infiltration, despite similar therapeutic outcomes. These findings demonstrate that extracellular matrix target selection significantly shapes the pharmacologic and safety profiles of intratumoral biologics, and identify hyaluronic acid anchoring as an alternative retention strategy with potential advantages.

bioengineering↗

bioRxiv2025

CD45 sequestration lowers the signaling threshold in lymphocytes and enhances anti-tumor immunity

CD45 plays a central role in immune signal regulation by controlling the spatial dynamics of phosphatase activity through steric segregation of its bulky rigid extracellular domain. To modulate CD45 activity, here we develop and characterize protein engineering approaches to induce multivalent clustering of CD45, effectively mimicking the endogenous local receptor sequestration during immune synapse formation. In doing so, we engineer a biologic that enables precise, tunable control over CD45 surface localization and activity. CD45 sequestration exhibited striking synergy when administered in combination with intratumorally anchored IL-12 therapy, markedly delaying tumor progression and extending survival in syngeneic murine melanoma and carcinoma models. Immune profiling revealed that CD8 T cells are essential mediators of this synergistic antitumor response. Mechanistically, IL-12 initiates a wave of antigen generation and T cell priming, while CD45 sequestration subsequently enhances tumor-specific CD8 T cell activation, expansion, and functional states within the tumor-draining lymph node. These findings suggest that CD45 sequestration lowers the activation threshold of T cells, broadens the tumor-reactive T cell repertoire, and therefore promotes more robust tumor-specific T cell responses. Altogether, we establish CD45 as a promising novel target for cancer immunotherapy, capable of potentiating strong anticancer immune responses.

immunology↗