Targeted IL-15-based Protein Fusion Complexes as Cancer Immunotherapy Approaches

Abstract

This mini review provides an overview and rationale for creating IL-15-based fusion protein complexes to be used as targeted immunotherapeutic agents. IL-15 stimulates proliferation and activation of CD8 + T and natural killer cells which result in augmentation of their anti-tumor activities. We have created ALT-803, an IL-15 superagonist complex which exhibits longer serum half-life, longer retention in lymphoid tissues, and better immunostimulatory and anti-tumor activities compared to native IL-15. When used alone or in combination with other immunotherapeutic molecules in various mouse tumor models, ALT-803 effectively reduces tumor burden and prolongs survival by stimulating the innate and adaptive arms of the immune system. To evaluate whether ALT-803 could be used as a protein scaffold to create IL-15-based tumor cell-specific molecules, we genetically fused it with a single chain anti-CD20 antibody derived from the variable regions of rituximab. This novel fusion protein exhibits enhanced anti-tumor activity compared to rituximab while maintaining IL-15 immunostimulating properties. Thus, ALT-803 may be exploited as a versatile scaffold to produce multivalent targeted fusion proteins to improve the anti-tumor efficacy of other therapeutic agents in the clinic. Interleukin-15 and ALT-803 Common gamma chain (γc) cytokines, which include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, have been studied extensively and shown to be promising as cancer immunotherapeutic agents 1. Recombinant IL-2 (rIL-2) has been approved for treatment of patients with metastatic renal cell carcinoma and melanoma more than two decades ago. Although rIL-2 can induce durable and major responses in a subset of patients 2,3 , the use of rIL-2 at the effective dose level causes severe side effects, such as capillary leak syndrome and hypertension, requiring extensive in-patient care during its administration 4. These treatment-induced side effects curtail the clinical utilities of rIL-2 as an immunotherapeutic drug. IL-15, a four helix γc cytokine, is structurally related to rIL-2 5. The two γc cytokines use the same IL-2/IL-15 receptor βγc (IL-2/15Rβγc) displayed on the surface of natural killer (NK) and T cells for signaling 1. However, IL-15 has been proven to stimulate anti-tumor immune responses of NK and T cells without the induction of IL-2-associated capillary leak syndrome, activation-induced cell death, and expansion of T regulatory cells 1,6. Thus, IL-15 is considered a promising immunotherapeutic for cancer treatment 3. IL-15 associates with IL-15 receptor α (IL-15Rα) on