Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2

Abstract

Interleukin-2 (IL-2) immunotherapy is an attractive approach in treating advanced cancer. However, by binding to its IL-2 receptor α (CD25) subunit, IL-2 exerts unwanted effects, including stimulation of immunosuppressive regulatory T cells (T) and contribution to vascular leak syndrome. We used a rational approach to develop a monoclonal antibody to human IL-2, termed NARA1, which acts as a high-affinity CD25 mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2-NARA1 complex revealed that NARA1 occupies the CD25 epitope of IL-2 and precisely overlaps with CD25. Association of NARA1 with IL-2 occurs with 10-fold higher affinity compared to CD25 and forms IL-2/NARA1 complexes, which, in vivo, preferentially stimulate CD8 T cells while disfavoring CD25 T and improving the benefit-to-adverse effect ratio of IL-2. In two transplantable and one spontaneous metastatic melanoma model, IL-2/NARA1 complex immunotherapy resulted in efficient expansion of tumor-specific and polyclonal CD8 T cells. These CD8 T cells showed robust interferon-γ production and expressed low levels of exhaustion markers programmed cell death protein-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin domain-3. These effects resulted in potent anticancer immune responses and prolonged survival in the tumor models. Collectively, our data demonstrate that NARA1 acts as a CD25-mimobody that confers selectivity and increased potency to IL-2 and warrant further assessment of NARA1 as a therapeutic.

Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

“…Indeed, surface plasmon resonance and P-STAT5 data using immune effector cells and Tregs from PBMC are supportive of a complete absence of CD25 affinity. CEA-IL2v exhibits a similar mechanism as described for the IL-2-S4B6 complex 11,53 and the human CD25-mimobody described recently, 54 including the lack of preferential activation of Tregs, reduced potency in triggering Fas-mediated apoptosis (AICD), superior tolerability compared with a wild-type IL-2-based immunocytokine and reduced clearance resulting in superior PK due to the lack of binding to the peripheral and endothelial CD25 sink 11 …”

Treg programming and therapeutic reprogramming in cancer

“…Similarly, blocking IL‐2 signalling may reprogramme Tregs, but IL‐2 signalling also stimulates natural killer cells and T‐cells; thus, its blockade may hinder the anti‐tumour activities of these cells. Efforts to direct these drugs exclusively to Tregs, such as with optimized antibodies that specifically deplete TI‐Tregs or engineered IL‐2 molecules that do not bind Tregs, may be critical to the success of targeting the IL‐2 pathway . Further work identifying target pathways that act selectively in TI‐Tregs combined with new strategies for selectively delivering drugs to TI‐Tregs will be needed to expand the repertoire of therapeutic options to reprogramme TI‐Tregs.…”

Injectable Polymeric Cytokine-Binding Nanowires Are Effective Tissue-Specific Immunomodulators

“…22-24 These have been widely characterized 25,26 and have garnered recent clinical interest with the development of humanized equivalents. 27 …”