(175ap) Optimizing Bias for Activation of Tumor-Reactive T Cell Subsets

Interleukin 2 (IL-2) is a powerful cytokine that plays a pivotal role in the development, maintenance, activation and proliferation of T cells. Upon encountering their cognate antigen, effector T cells require IL-2 stimulation for effective activation and proliferation. T regulatory cells (Tregs)—which are responsible for suppressing inflammatory responses and maintaining tolerance to self—are even more sensitive to IL-2 levels than effector T cells. In tumors, this increased sensitivity to IL-2 can allow Tregs to deplete the IL-2 levels within the tumor, which can prevent potentially tumor-reactive effector T cells from mounting an inflammatory immune response to clear the malignant cells.

Because IL-2 plays such an essential role in stimulating both pro- or anti-inflammatory responses, this cytokine has great potential for immune disease treatment. However, on its own it has an incredibly rapid clearance, and its concurrent activation of effector and regulatory T cells limits its therapeutic performance.

To address these shortcomings, we are engineering an IL-2 specific antibody that biases cytokine activity toward immunostimulatory functions. By modulating the interactions between IL-2 and its receptor, the antibody can eliminate the sensitivity advantage of Tregs. Moreover, complexing IL-2 with an antibody simultaneously prolongs cytokine half-life. Previous work using an anti-mouse IL-2 antibody demonstrated that IL-2/antibody complexes stimulated potent preferential expansion of effector T cells compared to Tregs, leading to inhibition of tumor growth in vivo.

We are using a yeast surface display system to engineer an antibody that binds human IL-2, with the aim of effectively tuning the cytokine/receptor interaction to favor activation of effector over regulatory T cells. Ultimately, this will allow the complex to potently drive effector-biased T cell expansion, resulting in dramatically increased therapeutic efficacy in the eradication of tumors, with a corresponding reduction in toxic side effects.