Engineered Cytokine-antibody Fusion for Targeted Expansion of Immune Effector Cells

Case ID:
C15802
Unmet Need
Global 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 Description
A 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 Development
The 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.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
METHODS AND MATERIALS FOR TARGETED EXPANSION OF IMMUNE EFFECTOR CELLS PCT: Patent Cooperation Treaty China 202080055260.2   6/26/2020     Abandoned
METHODS AND MATERIALS FOR TARGETED EXPANSION OF IMMUNE EFFECTOR CELLS PCT: Patent Cooperation Treaty European Patent Office 20833339.3   6/26/2020     Pending
METHODS AND MATERIALS FOR TARGETED EXPANSION OF IMMUNE EFFECTOR CELLS PCT: Patent Cooperation Treaty United States 17/622,539   12/23/2021     Pending
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For Information, Contact:
Vera Sampels
vsampel2@jhu.edu
410-614-0300
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