Oncotarget: Targeting engineered cytokine with interleukin to the neovasculature of tumors

Oncotarget recently published "Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors" by Mortensen, et al. which reported that there is a growing interest in the antibody-based delivery of cytokines to the tumor environment as a means to boost the anti-cancer activity of tumor-resident T cells and NK cells.

Here, the authors described the expression and characterization of fusion proteins, featuring the L19 antibody and an engineered cytokine with interleukin-2 and interleukin-15 properties.

The cytokine moiety was fused either at the N-terminal or at the C-terminal extremity and both fusion proteins showed a selective tumor accumulation in a quantitative biodistribution experiment.

The N-terminal fusion inhibited tumor growth in immunocompetent mice bearing F9 carcinomas or WEHI-164 sarcomas when used as a single agent.

These results indicate that the antibody-based delivery of engineered cytokines to the tumor neovasculature may mediate a potent anticancer activity.

Dr. Michael R. Mortensen from The Department of Chemistry and Applied Biosciences (D-CHAB) at The Institute for Pharmaceutical Sciences (IPW) in Zurich, Switzerland said, "Cancer immunotherapy relies on the activation of certain leukocytes (most typically, T cells and/or natural killer cells), with the aim to induce a selective biocidal activity against tumor cells."

IL2 muteins may alter the interaction of the cytokine with one or more of the IL2 receptor subunits, thus altering the selectivity towards the intermediate affinity receptor or towards the high-affinity receptor.

Since regulatory T cells predominantly express the high-affinity receptor, the selective activation of the intermediate affinity receptor has attracted considerable research efforts.

Figure 4: Activity of Neo™-L19 in F9 teratocarcinoma or WEHI-164 fibrosarcoma tumor bearing mice. (A) F9 teratocarcinoma. Left: Tumor bearing mice received 3 injections (↓) of Neo™-L19, Neo™-KSF or saline (PBS) when the tumors reached an average size of 90 mm³. The data is represented as the mean ± SD. Statistical analysis was performed by two-way ANOVA with post Bonferroni test (Not significant P > 0.05, ^*P < 0.05, ^**P < 0.01, ^***P < 0.001, ^****P < 0.0001). All the immunocytokine treatments were statistically different from the saline treatment on day 14 (^****P < 0.0001). On day 20, Neo™-L19 10 μg per inj (^**P < 0.01) and Neo™-L19 100 μg per inj (^****P < 0.0001) were different from the Neo™-KSF (100 μg per inj) group. Right: Body weight changes during the treatment represented as the mean ± SD. (B) WEHI-164 fibrosarcoma. Left: Tumor bearing mice received 2 equimolar injections (↓) of Neo™-L19, Neo™-KSF, His₆-Neo™ or saline (PBS) when the tumors reached an average size of 90 mm³. The data is represented as the mean ± SD. On day 16, the Neo™-L19 (^****P < 0.0001) and Neo™-KSF (^*P < 0.05) groups showed a significant difference to the saline group. On day 16, Neo™-L19 was different from the His₆-Neo™ (^***P < 0.001) and Neo™-KSF (^*P < 0.05) groups. On day 17, Neo™-L19 and Neo™-KSF was not significantly different (P > 0.05). Right: Body weight changes during the treatment represented as the mean ± SD. Only significant differences between treatment groups have been indicated. ^¥only two mice remaining in the group. CR: complete response.

In a second approach, an increased selectivity towards the intermediate affinity IL2 receptor was achieved by blocking the interaction with CD25 either through IL2 mutations or by antibody blockade of the IL2 epitope involved in CD25 binding.

The Oncotarget authors described a series of engineered cytokines, which displayed biological features intermediate between those of IL2 and of IL15. IL15 interacts with CD122 and CD132 like IL2 but recognizes a different alpha subunit.

One of the new computationally designed cytokine variants, termed by the authors Neoleukin™-2/15, exhibited an increased affinity towards the receptor components shared by IL2 and IL15, with a complete absence of CD25 binding. Moreover, the newly engineered cytokine was much more stable compared to wild-type IL2.

The Mortensen Research Team concluded in their Oncotarget Research Paper that for certain cytokines the fusion with a tumor-homing antibody allows the creation of novel biopharmaceuticals, which display a preferential uptake in tumor lesions and which perform substantially better than the corresponding nontargeted cytokine in immunocompetent mouse models.

These authors and others have reported that not all cytokine payloads can be efficiently delivered to the tumor by fusion with antibodies.

Cytokine trapping at a low dose has been reported for fusion proteins based on interferon-gamma, but also for IL15 fusions.

Neo™-L19 is not glycosylated and the authors were pleased to see how the L19-based targeted delivery of the engineered IL2 and IL15 mimic led to an improved therapeutic effect for the F9 teratocarcinoma model. The contribution of L19-based targeting to an increased therapeutic index was less striking in the WEHI-164 model.

Collectively, the results presented indicate that a new fusion protein could be created, which displayed an excellent performance in biodistribution studies and which mediated a potent anticancer activity in two immunocompetent mouse models of cancer when used as a single agent.

The results suggest that this product, or similar fusion proteins featuring an N-terminal fusion in the diabody format, may deserve to be investigated in clinical trials.

"The results suggest that this product, or similar fusion proteins featuring an N-terminal fusion in the diabody format, may deserve to be investigated in clinical trials"

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DOI - https://doi.org/10.18632/oncotarget.27772

Full text - https://www.oncotarget.com/article/27772/text/

Correspondence to - Michael R. Mortensen - michael.mortensen@pharma.ethz.ch

Keywords - immunotherapy, immunocytokines, EDB of fibronectin, antibody-cytokine fusion proteins, engineered cytokine

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