Targeting oxMIF Signals Promise as New Immuno-Oncology Option for mCRC

oxMIF as a cancer immuno-oncology target shows potential in the treatment of patients with metastatic colorectal cancer (mCRC). The anti-oxMIF antibody ON203 demonstrated direct antitumorigenic effects by blocking the biologic function of oxMIF.

Further, the agent reduced tumor cell proliferation and angiogenesis by immunomodulation of the tumor microenvironment.

The macrophage migration inhibitory factor (MIF) is 1 of the first pleiotropic, proinflammatory cytokines. MIF drives tumor growth, angiogenesis, and metastases, and more recently, it has shown to be a critical driver of innate tumor immunity. Despite significant research efforts, experts like Randolf Kerschbaumer, MD, say that targeting MIF directly has proven elusive.

“Historical efforts to target MIF directly have not been successful since MIF is so abundant in healthy tissues,” said Kerschbaumerm, chief executive officer of OncoOne, in an interview with Targeted OncologyTM. “We simply believe that MIF is most likely inert and undruggable by both small molecules and antibodies, so we created ON203 to target oxMIF, which is only found at the tumor and not in healthy tissues.”

At sites of inflammation, MIF, which is found in abundance in healthy tissues, aggregates and undergoes a change to become oxidized MIF, also known as oxMIF.Optimized monoclonal antibodies were designed to target only oxMIF and reverse pro-tumorigenic cascades driven by MIF.

During the 2022 Society for ImmunoTherapy of Cancer Therapy Congress, research from ON203, a disease-related and druggable isoform of MIF which was tested in tumors derived from patients with mCRC, was shared in a poster presentation.

Preclinical models evaluating ON203 have shown promising data as the agent elicited superior in vivo efficacy compared with C0008 when used in a prophylactic mouse model of prostate cancer.

To further determine the single agent potential of ON203, investigators assessed the agent’s effect on tumoroids from 5 patients with colorectal cancer. Patients were administered ex vivo treatment of 10nM ON203.

With 1 low dose application, ON203 demonstrated single agent activity in tumoroids from 4 of the 5 patients evaluated. However, the tumor cell death that was observed correlated with the activation of key immune effector cells including NKs, NKTs, and macrophages.

“I think the key takeaway from this dataset is that oxMIF is a new immuno-oncology target with significant potential as a standalone therapy for the treatment of patients with colorectal cancer.With tumoroids better predictors of actual clinical outcomes than animal models, these data give the team at OncoOne a great deal of confidence as we prepare to enter clinical trials,” added Kerschbaumer.

ON203 also induced an increase in NK cell numbers in patients whose tumors responded to treatment. The expression of activation marker Granzyme B and the deregulation marker CD107a increased in those who responded to ON203 on NK and NKT cells. The 1 patient who did not respond showed no expression changes.

Also, treatment with ON203 led to a polarization of macrophages towards an anti-tumor phenotype in responders. This was demonstrated by an increase in HLA-DR and FcyRIII CD16 on macrophages which were determined by flow cytometry 24 hours after treatment.

Based on these data, ON203 shows potential as a standalone therapy or in combination with immune checkpoint inhibitors or anti angiogenic agents in patients with solid tumors. OncoOne is now planning to begin a phase 1 trial which will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ON203 in patients with solid tumors, including colorectal cancers. This trial is expected to begin in 2023.

“Looking ahead, MIF has been implicated in practically all solid tumors and even some hematologic malignancies. We feel that the science points solid tumors as the best targets for ON203, especially colorectal, breast, lung, and ovarian cancers.We are hopeful that the single agent activity of ON203 will be mirrored in the clinic, and we certainly believe that ON203 will be combinable with immune checkpoint inhibitors, anti-angiogenic therapies, and chemotherapeutics,” concluded Kerschbaumer.

_REFERENCE:

_{Maurer B, Mirkina I, Mayer J, et al. ON203: A new antibody targeting the oxidized form of macrophage migration inhibitory factor (oxMIF) exerts antitumorigenic activity and modulate. Presented at Society for Immunotherapy of Cancer 2022 Annual Meeting; November 8-12, 2022; Boston, Massachusetts.}