SUMMARY:
UCLA researchers in the Department of Bioengineering have developed valency-mediated cytokine improvements, enabling the development of significantly more specific cytokine therapies.
BACKGROUND:
Cytokine therapy, in the growing arsenal of immunotherapies, aims to enhance, suppress, or alter the function of certain immune cells in a highly specific manner. Cytokines play an integral role in the cellular communication of the immune system, modulating both innate and immune responses. Many advances have been made to increase the specificity of cytokines for specific target cell populations through protein engineering. An example of the beneficial translation of protein engineering can be seen in the case of interleukin-2 (IL-2). Low-dose IL-2 leads to the expansion of regulatory T cells, with beneficial effects in several autoimmune diseases. Engineered binding affinity changes for IL-2Ra over IL-2Rb have led to marked efficacy increases and reductions in toxicity over native IL-2. Unfortunately, the effectiveness of protein-engineered cytokines is stymied by the complexity of their binding to target cells and their activation mechanisms. Significant off-target effects are still seen because of signaling through other IL-2-responsive cellular targets such as NK cells. Therefore, a need exists to further improve the selectivity of IL-2 and other cytokine therapies.
INNOVATION:
UCLA researchers in the Department of Bioengineering have developed an alternative route toward obtaining cell-selective cytokines. By profiling various immune cell populations and comparing the responses to a computational model, they determined how cytokine structure influences response. While protein sequence changes can alter the relative affinity of cytokines toward different receptors, these changes do not provide selectivity between cells expressing different receptor amounts. Due to the observation that on-target and off-target cells express the same receptors, just in varying amounts, protein sequence changes can only achieve an upper limit of selectivity. Instead, the researchers found that changes in cytokine valency could improve selectivity based on receptor density. High valency effectively enabled enhanced selectivity toward cells with high receptor abundance; bivalent cytokines increased selective regulatory T cell binding up to 5-fold compared to their monovalent counterparts. Furthermore, researchers predicted and experimentally verified that tetravalent cytokines produce even greater cell selectivity. This approach may allow cytokine treatments in many pharmaceutical pipelines to achieve greater target specificity with reduced toxicities.
POTENTIAL APPLICATIONS
• Further improvement of cytokine specificity
• Immunosuppressive cytokine therapy (e.g., autoimmune diseases, transplant rejection)
• Immune stimulatory cytokine therapy (e.g., cancer immunotherapy)
ADVANTAGES:
• First to show the potential superiority of tetravalent immune-modulatory cytokines
• Multiple implementation strategies to obtain high-valency cytokines
• Expected to be synergistic with affinity changes through alterations in cytokine sequence
DEVELOPMENT-TO-DATE:
A panel of IL-2 designs, including both muteins and Fc fusion structures, were profiled. Modeling verified that the selectivity advantages of bivalent Fc fusions are conferred through avidity effects. A new tetravalent Fc fusion design was demonstrated to have superior regulatory T cell selectivity compared to all existing IL-2–Fc fusions.
Related Papers:
bioRxiv 2022, Dec, (https://www.biorxiv.org/content/10.1101/2021.07.03.451002v2)
Cell Reports 2021, Apr, 35;4 (https://doi.org/10.1016/j.celrep.2021.109044)