Enhancing Cancer Immunotherapy: The Development and Evaluation of IL2v-Based Tumor-Targeted Immunocytokines

IL-2 therapies have shown potential in cancer treatment but are limited by toxicity and design constraints, such as the challenges posed by IL-2-based immunocytokines. A new class of immunocytokines has been engineered to address these issues, featuring a monomeric design with a single IL-2 variant (IL2v) that cannot bind to CD25, fused to a tumor-targeting antibody with a novel Fc mutation to prevent FcγR and C1q binding.

Two specific immunocytokines, CEA-IL2v and FAP-IL2v, were developed to target carcinoembryonic antigen (CEA) and fibroblast activation protein (FAP), respectively. They were designed to bind with high affinity to their respective tumor-associated antigens without binding to CD25, thus avoiding preferential activation of regulatory T cells (Tregs) and reducing pulmonary toxicity.

In vitro testing showed that these immunocytokines activate and expand natural killer (NK) cells and CD8+ T cells, maintaining bioactivity through IL-2Rβγ. They also enhance the cytotoxic activity of NK cells when combined with antibodies capable of antibody-dependent cellular cytotoxicity (ADCC). In vivo studies in mice demonstrated improved safety, pharmacokinetics, and tumor targeting for CEA-IL2v and FAP-IL2v. Notably, they showed high expansion and activation of immune effector cells, including NK and CD8+ T cells, and a strong skewing of the CD4:CD8 ratio towards CD8+ T cells in various tissues.

MicroSPECT/CT imaging confirmed effective FAP-mediated tumor targeting with low uptake in normal tissues and lymphoid tissues. Anti-tumor efficacy was observed in syngeneic tumor models, and the immunocytokines were shown to significantly enhance the efficacy of ADCC-competent antibodies in SCID mice transgenic for human CD16A.

In conclusion, CEA-IL2v and FAP-IL2v offer enhanced safety, pharmacokinetics, and tumor targeting without preferential induction of Tregs due to their unique design. They retain the ability to activate and expand NK and CD8+ effector T cells, supporting their potential for further nonclinical and clinical investigation in cancer immunotherapy. Clinical trials for CEA-IL2v are anticipated.