Anti-oxMIF platform.

oxMIF: The Secret of targeting MIF

MIF – macrophage migration inhibitory factor

Macrophage migration inhibitory factor (MIF) is a pleiotropic chemokine consisting of three identical subunits, that is driving tumorigenic cell signaling and exerting immunomodulatory activities in the tumor microenvironment (Mitchell et al., 2002). In patients, MIF has been associated with high tumor burden, increased metastasis risk, and poor prognosis (Krockenberger et al., 2012).

MIF is also a pro-inflammatory cytokine and counter-regulator of exogenous and endogenous glucocorticoids (Calandra and Roger, 2003). It is implicated in acute and chronic inflammatory conditions, such as inflammatory bowel disease, systemic lupus erythematosus or rheumatoid arthritis.

MIF is markedly different from other cytokines and chemokines because it is constitutively expressed, stored in the cytoplasm and is present in the circulation of healthy subjects (Roger et al., 2017). Due to its ubiquitous nature, MIF may be considered as an inappropriate target for therapeutic intervention.

oxMIF – oxidized macrophage migration inhibitory factor

The founders of OncoOne discovered a disease-related isoform of MIF, designated oxMIF (oxidized MIF) (Thiele et al., 2015). OxMIF is generated by a posttranslational modification of MIF in inflammatory processes and tumorigenesis. Unlike MIF, oxMIF is differentially expressed in healthy and diseased tissue and can be detected in inflamed tissues and solid tumors (Thiele et al., 2015; Schinagl et al., 2016). Importantly, the post-translational modification leads to a structural transformation that exposes epitopes in the MIF trimer that are otherwise inaccessible to antibodies in the center of the trimer. Targeting oxMIF as the disease related isoform of MIF, overcomes the challenges of targeting MIF and makes oxMIF ideal for therapeutic intervention.

Biotherapeutics targeting oxMIF

OncoOne’ generates novel and highly potent biotherapeutics targeting oxMIF to treat underserved patients suffering from solid tumors and chronic inflammatory diseases.

Anti-oxMIF platform using our second generation engineered anti-oxMIF antibodies

Anti-oxMIF antibodies in oncology

OncoOne has developed multiple novel oxMIF-specific antibodies advancing to the clinic:

  • Clinical candidate ON203 is a bioengineered monoclonal anti-oxMIF antibody designed to exert cytotoxic functions by inducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) for high therapeutic potential in solid tumors.
  • Clinical candidate ON102 is a radioimmunoconjugate companion diagnostic (ON102) to provide a non-invasive approach to detect oxMIF-rich tumors. ON203 and ON102 will be developed in parallel.
  • Research program ON-02 is a radioimmunoconjugate for therapeutic application.

Based on these different mechanisms, the drug candidates will enable both monotherapies and novel combinatorial treatment approaches for patients suffering from solid tumors of the colon, ovary, pancreas, and lung. Compared to the published first generation oxMIF antibodies, all OncoOne antibody-based modalities have been significantly optimized in terms of pharmacokinetics, pharmacodynamics and bioavailability.

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Anti-oxMIF antibody for inflammation

In the course of research program ON-04, OncoOne has generated a bioengineered non-cytotoxic monoclonal anti-oxMIF antibody that also possesses optimal pharmacokinetics, pharmacodynamics and bioavailability and is intended for use for treatment of chronic inflammatory and autoimmune diseases like inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematodes and asthma.

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