SUMMARY:
UCLA researchers in the Department of Bioengineering have developed a novel strategy to engineer multivalent cytokine complexes that significantly increase their selectivity towards activating effector or regulatory immune cells and reduce off-target effects in immunotherapy treatments for cancer and autoimmune diseases.
BACKGROUND:
In recent years, the use of immunotherapies for the treatment of cancers and autoimmune diseases has steadily grown. Cytokines, secreted small molecules, play a critical role in cellular communication within the immune system, modulating both the innate and adaptive immune responses. As such, scientists have been researching the use of cytokines for selective activation, suppression, or change in function of immune cells. So far, cytokine therapy has been approved for the treatment of metastatic melanoma using recombinant interleukin-2 (IL-2), an integral cytokine that stimulates differentiation of T cells. Low-dose IL-2, which preferentially increases the abundance of regulatory T cells, has also been explored as a therapy for several autoimmune diseases. However, the use of IL-2 and other cytokines has been largely limited by its poor specificity, which can lead to detrimental side effects in patients. Therefore, there is urgent need for advances in protein engineering to increase the specificity of cytokines towards specific target cell populations to yield safer cytokine-based treatments.
INNOVATION:
UCLA researchers led by Dr. Aaron Meyer in the Department of Bioengineering have developed a novel method of altering cytokine selectivity for more potent on-target signaling and reduced off-target effects. Previously, the Meyer group discovered that changes in cytokine valency, or the number of cytokines within a complex, could alter the avidity of cytokines and increase their selectivity. This allows, for example, for engineered tetravalent IL-2 complexes to be more selective for regulatory T cells than monovalent or bivalent IL-2–Fc fusions. Using high-throughput profiling data, UCLA researchers found that selectivity can be further enhanced by using individual monomers of heterogeneous composition in a multivalent cytokine complex. They also found that heterogeneous multivalency allows making other non-Treg-selective cytokines Treg-selective, such as IL-7, potentially providing a platform to decouple the signal and cell target of many cytokines. This approach may allow stymied cytokine treatments in many pharmaceutical pipelines to achieve greater target specificity with low incidence of traditional toxicities and side-effects.
POTENTIAL APPLICATIONS:
• Immunosuppressive cytokine therapy for autoimmune diseases
• Immune stimulatory cytokine therapy for cancer treatments
ADVANTAGES:
• Increased cytokine specificity to reduce the off-target effects of immunotherapies
• Multiple implementation strategies to increase potency of IL-2 cytokines or make non-specific cytokines selective for Tregs
DEVELOPMENT-TO-DATE:
Cell selectivity of various cytokine designs has been predicted with a computational model. These designs have been tested in vitro, exhibiting the expected selectivity improvements.
Related Papers (from the inventors only):
Multivalent, asymmetric IL-2-Fc fusions provide optimally enhanced regulatory T cell selectivity. Brian Orcutt-Jahns, Peter C. Emmel, Eli M. Snyder, Scott D. Taylor, Aaron S. Meyer bioRxiv 2021.07.03.451002.