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ON203: A new antibody targeting the oxidized form of macrophage migration inhibitory factor demonstrates antitumorigenic activity and TME modulation in patient-derived CRC tumoroids
Background
The tumor microenvironment (TME) determines therapeutic response, and its modulation can help to overcome therapeutic resistance. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine whose overexpression is associated with tumor aggressiveness, metastasis, and disease progression. Due to its ubiquitous nature, MIF is considered an unsuitable target for therapeutic intervention. However, a disease-related isoform of MIF, oxidized MIF (oxMIF), is specifically present in solid tumor tissue including colorectal and pancreatic cancer. A first-generation anti-oxMIF monoclonal antibody (mAb) demonstrated an acceptable safety in a phase 1 clinical trial, including 25 patients with colorectal carcinoma (CRC). Tissue penetration and target occupancy analyses demonstrated specific binding of imalumab to oxMIF in CRC liver metastases. Biopsies further revealed that imalumab interferes with the PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Due to imalumab’s strong hydrophobicity and tendency to aggregate, we have developed ON203, a bioengineered second-generation anti-oxMIF mAb with highly improved physicochemical and biological properties, designed to exert better tumor retention and enhanced Fc-mediated effector functions resulting in higher efficacy in animal models. Our current results on ON203’s effect on freshly isolated 3D tumoroids from CRC patients support our planned first-in-human, phase 1, open-label, dose-escalation study to assess safety, tolerability, PK, and pharmacodynamics of the anti-oxMIF antibody ON203 in patients with malignant solid tumors.
Methods
Fresh 3D tumoroids with intact TME were isolated from five G2- or G3-graded colorectal adenocarcinoma patients, aged between 55 and 67 years comprising both genders, and treated with ON203 or isotype control. Tumor cell death was assessed by high-content 3D computational bioimaging and changes in tumor-associated immune cells were analyzed by flow cytometry, e.g. for expression of Granzyme B, CD107a, CD16, CD32 or HLA-DR on CD8 + T cells, NK or NKT cells as well as on M1 and M2 macrophages.
Results
Tumoroids from four out of five tested CRC patients responded to ON203 treatment with an up to 55 % increased tumor cell killing compared to untreated and isotype IgG-treated tumoroids. Treatment with ON203 resulted in elevated total immune cell numbers. Intriguingly, the three best responding patient tumoroids showed an up to threefold increase in M1 macrophages and NK cells. Tumor cell killing correlated with NK cell activation and degranulation markers (e.g. Granzyme B and CD107a). These data imply a potential for ON203 in changing the TME towards an enhanced therapeutic response.
Conclusions
Targeting oxMIF, the disease-specific isoform of MIF, with ON203 mAb induces tumor cell killing, modulates the immune cell composition of the TME and increases NK cell activity. These findings are in line with in vivo efficacy models. Therefore, ON203 has a high potential to become a new treatment option for patients with colorectal cancers as a standalone therapy or in combination with checkpoint inhibitors, chemotherapeutics, anti-angiogenic drugs, or kinase inhibitors.
Legal entity responsible for the study
The authors.
Funding
This study is funded by OncoOne Research & Development.
Disclosures
B. Maurer: Travel / Accommodation / Expenses: OncoOne Research & Development GmbH; Full / Part-time employment: OncoOne Research & Development GmbH. I. Mirkina: Shareholder / Stockholder / Stock options: OncoOne Research &Development GmbH, OncoOne Research &Development GmbH, OncoOne Research &Development GmbH; Full / Part-time employment: OncoOne Research &Development GmbH, OncoOne Research &Development GmbH, OncoOne Research &Development GmbH. M. Thiele: Shareholder / Stockholder / Stock options: OncoOne ; Full / Part-time employment: OncoOne; Officer / Board of Directors: OncoOne.
