US20260083855
2026-03-26
Human necessities
A61K47/6813
The invention pertains to immunoconjugates, which are complexes combining a mutant interleukin-2 (IL-2) polypeptide and an antibody targeting PD-1. These immunoconjugates are designed to enhance immune responses against tumors while minimizing adverse effects associated with traditional IL-2 therapies. The application includes polynucleotide sequences encoding these immunoconjugates, as well as vectors and host cells that incorporate these sequences. Additionally, methods for producing these conjugates and their potential pharmaceutical applications are explored.
IL-2 is a crucial cytokine involved in the growth and regulation of immune cells, particularly T cells. It facilitates the proliferation of cytotoxic T lymphocytes and natural killer cells, contributing to immune defense and antitumor activities. However, IL-2 also plays a role in maintaining immune tolerance through activation-induced cell death (AICD) in T cells and supporting regulatory T cells (Tregs), which can suppress immune responses. These dual functions of IL-2 present challenges in its use for cancer immunotherapy.
While IL-2 has been approved for treating certain cancers, such as metastatic renal-cell carcinoma and malignant melanoma, its use is limited by severe side effects, including vascular leak syndrome (VLS). VLS results from increased vascular permeability, leading to complications like pulmonary edema and cardiovascular issues. Efforts to mitigate these effects include altering IL-2 to reduce its toxicity and enhance its efficacy, such as through mutations that decrease its interaction with IL-2 receptors on non-target cells.
To address these challenges, mutant IL-2 polypeptides have been engineered to reduce unwanted interactions with IL-2 receptors, particularly the CD25 subunit associated with Tregs. Specific mutations, such as substituting certain amino acids, have been shown to diminish binding to CD25, thus reducing the activation of Treg cells and potentially improving the antitumor effectiveness of IL-2. These modifications aim to optimize IL-2's therapeutic potential while minimizing its immunosuppressive effects.
The invention further explores the use of immunoconjugates that target IL-2 to tumors via antibodies specific to antigens expressed on tumor cells. This targeted approach could enhance the concentration of IL-2 at tumor sites, increasing its therapeutic efficacy while reducing systemic side effects. Existing research supports the potential of such immunoconjugates to improve cancer immunotherapy outcomes by focusing immune activation directly at the tumor site.