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Preclinical Evaluation of ON203, A Novel Bioengineered mAb Targeting Oxidized Macrophage Migration Inhibitory Factor
Gregor Rossmueller1, Irina Mirkina1, Barbara Maurer1
1OncoOne Research & Development GmbH, Vienna, Austria.
Abstract:
High levels of macrophage migration inhibitory factor (MIF) in patients with cancer are associated with poor prognosis. Its redox-dependent conformational isoform, termed oxidized MIF (oxMIF), is a promising tumor target due to its selective occurrence in tumor lesions and at inflammatory sites. A first-generation anti-oxMIF mAb, imalumab, was investigated in clinical trials in patients with advanced solid tumors, where it was well tolerated and showed signs of efficacy. However, imalumab has a short half-life in humans, increased aggregation propensity, and an unfavorable pharmacokinetic profile. Here, we aimed to optimize imalumab by improving its physicochemical characteristics and boosting its effector functions. Point mutations introduced into the variable regions reduced hydrophobicity and the antibodies' aggregation potential, and increased plasma half-life and tumor accumulation in vivo, while retaining affinity and specificity to oxMIF. The introduction of mutations into the Fc region known to increase antibody-dependent cellular cytotoxicity resulted in enhanced effector functions of the novel antibodies in vitro, whereas reduced cytokine release from human peripheral blood mononuclear cells in the absence of target antigen by the engineered anti-oxMIF mAb ON203 versus imalumab reveals a favorable in vitro safety profile. In vivo, ON203 mAb demonstrated superior efficacy over imalumab in both prophylactic and established prostate cancer (PC3) mouse xenograft models. In summary, our data highlight the potential of the second-generation anti-oxMIF mAb ON203 as a promising immunotherapy for patients with solid tumors, warranting clinical evaluation.
Insights
A new antibody, ON203, targeting oxidized macrophage migration inhibitory factor (oxMIF) shows improved efficacy and safety over the first-generation antibody imalumab for treating solid tumors.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- High levels of macrophage migration inhibitory factor (MIF) correlate with poor cancer prognosis.
- Oxidized MIF (oxMIF) is a tumor-specific target, and the first-generation antibody imalumab showed preliminary efficacy but had limitations.
- Imalumab's short half-life, aggregation, and unfavorable pharmacokinetics hindered its therapeutic potential.
Purpose of the Study:
- To engineer a second-generation anti-oxMIF monoclonal antibody (mAb) with improved physicochemical properties and enhanced effector functions.
- To optimize imalumab by modifying variable and Fc regions to improve half-life, reduce aggregation, and increase anti-tumor activity.
- To evaluate the efficacy and safety profile of the novel antibody ON203 compared to imalumab.
Main Methods:
- Point mutations were introduced into the variable regions of imalumab to reduce hydrophobicity and aggregation, and into the Fc region to enhance antibody-dependent cellular cytotoxicity (ADCC).
- The engineered antibody, ON203, was characterized for affinity, specificity, aggregation potential, and effector functions in vitro.
- In vivo efficacy and safety were assessed using prostate cancer (PC3) mouse xenograft models, comparing ON203 to imalumab.
Main Results:
- Mutations successfully reduced antibody aggregation and improved plasma half-life and tumor accumulation in vivo, while maintaining oxMIF binding.
- ON203 demonstrated enhanced in vitro effector functions and a favorable in vitro safety profile with reduced cytokine release compared to imalumab.
- ON203 exhibited superior efficacy over imalumab in both prophylactic and established prostate cancer mouse models.
Conclusions:
- The second-generation anti-oxMIF mAb ON203 possesses improved pharmacokinetic and pharmacodynamic properties compared to imalumab.
- ON203 shows enhanced anti-tumor efficacy and a favorable safety profile, indicating its potential as a novel cancer immunotherapy.
- ON203 warrants further clinical evaluation for the treatment of patients with solid tumors.
