Unmet NeedGlobal revenue from the cytokine therapeutics market was valued at approximately $16.5 billion in 2018, and cytokine immunotherapy is a promising field of anti-cancer treatments for a broad range of cancer types. In particular, interleukin-2 (IL-2) therapy is shown to stimulate anti-cancer immunity. However, IL-2 activates contradictory immune responses by promoting both the activity of immune effector cells (which stimulate immune activity), and regulatory T cells (which suppress immune activity), resulting in harmful off-target effects such as severe vascular leak syndrome, which can lead to edema and organ failure. Additionally, IL-2 is plagued by a low rate (5-10%) of durable responses in patients and a short serum half-life (<5min). IL-2 immunotherapy can be improved by forming complexes between the cytokine and an antibody called S4B6. IL-2/S4B6 complexes are able to promote the activity of effector cells while minimizing activation of regulatory T-cells, thus improving the anti-cancer response and avoiding the adverse suppressive effects seen with unbound IL-2. However, clinical translation of the IL-2/S4B6 complex is hindered by logistical hurdles such as ensuring complex stability to avoid dissociation of the complex into free IL-2, which can induce dangerous toxicities and has poor pharmacokinetic properties. Also, the S4B6 antibody binds to mouse IL-2, but has limited reactivity with human IL-2 (hIL-2). Thus, there is an unmet need for an IL-2/antibody complex that is compatible with hIL-2, has a stable complex configuration and clinically relevant serum half-life, and selectively engages effector cells to minimize off-target toxicities.
Technology DescriptionA human analog form of S4B6 was isolated (denoted ‘602’) and conjugated to hIL-2, creating a hIL-2/602 complex that served as the basis for designing a single-chain IL-2/602 fusion construct. Synthesizing the complex as a single-chain construct prevents the complex from dissociating into free IL-2 and an antibody, thus avoiding the toxicities typically found with unbound IL-2 or dissociated IL-2/antibody complexes. Also, the single-chain format extends the serum half-life of the cytokine, allowing IL-2/602 to target tissue for a longer period of time, which can improve durability of the patients’ immune response. Unlike unbound IL-2, which nonspecifically upregulates both immune effector cell and regulatory T cell activities, the complex selectively promotes immune effector cell activity. This activates a powerful anti-cancer response that is not suppressed by regulatory T cells, and reduces the adverse side effects associated with standard IL-2 therapy. The IL-2/602 single-chain construct also takes advantage of the universal importance of the immune response in cancer, and thus can be used to treat a wide range of malignancies. Moreover, this approach can be readily coupled with other immunotherapeutic strategies such as vaccines, adoptive cell transfer, and immune checkpoint blockade.
Stage of DevelopmentThe inventors developed a novel single-chain fusion construct comprising hIL-2 and the 602 antibody. In vitro binding and signaling studies demonstrated that the complex enhanced interaction with and activation of immune effector cells compared to regulatory T cells, confirming the complex’s ability to preferentially stimulate the immune response. In vivo studies with a mouse melanoma model demonstrated that immune effector cell activity increased after injection of the IL-2/602 complex, and that a twice-weekly dosage significantly inhibited tumor growth, verifying the viability of the approach to stimulate an anti-cancer immune response.
