oxMIF – the Key to Targeting MIF
MIF – Macrophage migration inhibitory factor
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine consisting of three identical subunits that drives tumorigenic cell signaling and exerts immunomodulatory activities in the tumor microenvironment (Mitchell et al., 2002; Mitchell et al., 2020). In cancer 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 and rheumatoid arthritis.
MIF is markedly different from other cytokines because it is constitutively expressed and stored in the cytoplasm and is present in the circulation of healthy subjects (Roger et al., 2017). Due to its ubiquitous nature, MIF has been considered a critical yet “undruggable” target for therapeutic intervention because entities targeting MIF are intercepted by excess MIF protein in circulation and in normal tissue, therefore impairing beneficial effects in diseased tissue.
oxMIF – oxidized Macrophage migration inhibitory factor
The founders of OncoOne discovered a disease-related isoform of MIF, which they named “oxMIF” (oxidized MIF) (Thiele et al., 2015), because it is generated in the pro-oxidative microenvironment in inflammatory processes and tumorigenesis. In contrast to MIF, which is expressed in healthy and diseased tissues, oxMIF is formed by post-translational modification in inflamed tissue 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 homotrimer that are otherwise inaccessible to antibodies in the center of the trimer. Targeting oxMIF as the disease related isoform of MIF therefore overcomes the previous significant challenges associated with targeting MIF, making it an ideal candidate for therapeutic intervention in an array of high-need indications.
Antibody based modalities targeting oxMIF
OncoOne generates novel and highly potent antibody modalities targeting oxMIF to treat underserved patient populations living with solid cancers and/or chronic inflammatory diseases.
In tumor tissue and at sites of inflammation MIF is converted to oxMIF by posttranslational modification. Through this modification, MIF undergoes a structural change, making epitopes in the central channel of the trimer accessible to antibodies. Since this process is confined to a diseased tissue, oxMIF, unlike MIF, can be specifically targeted in tumors and inflamed tissues.
Our proprietary anti-oxMIF antibodies
OncoOne has developed multiple, novel oxMIF-specific antibodies advancing toward the clinic:
• Clinical candidate ON203 is a second generation, bioengineered anti-oxMIF antibody designed for optimal tumor penetration & tumor retention. ON203 inhibits MIF-mediated pro-tumorigenic signaling and exerts cytotoxic functions by inducing antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) for high therapeutic potential in solid tumors.
• Research program ON-05 comprises an anti-oxMIF radiotherapy utilizing OncoOne’s proprietary PreTarg-it® platform.
• ON102 is a radioimmunoconjugate designed to provide a non-invasive approach for diagnostic applications (pan-cancer diagnostic).
Based on these different mechanisms, our drug candidates will enable both monotherapies and innovative combination 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.
ON203 specifically binds and neutralizes oxMIF and thereby inhibits MIF-mediated, pro-proliferative and anti-apoptotic tumor cell signaling. Further, ON203 was designed to mediate ADCC and ADCP.
Unlocking new therapeutic approaches
OncoOne’s PreTarg-it® technology is a modular platform utilizing bispecific antibodies for optimized biodelivery of payloads. Size, geometry and valency of the bispecific antibodies are designed for optimal penetration and retention within tumors.
First, the bispecific antibody is injected and accumulates in the tumor, while unbound antibodies are decomposed end excreted within a few days following administration. Then, a specific and highly affine second construct containing the payload, is administered and binds to the bispecific antibody in the tumor. This approach provides higher tumor to non-tumor ratios and improved therapeutic indexes than traditional approaches. The modular “target X × payload Y” concept enables targeting of tumor antigens with payloads of different substance classes, like radionuclides, immunomodulators and (encapsulated) toxins.
• Research program ON-05 is an oxMIF specific pretargeted radioimmunotherapy, utilizing OncoOne’s proprietary PreTarg-it® platform.
• Research programs ON-06 and ON-07 are therapies against undisclosed solid tumor targets utilizing the PreTarg-it® platform.
The PreTarg-it® platform: In a first step a specifically designed bispecific antibody is injected that accumulates in the tumor. In a second step, a high affinity construct containing the payload is administered which ligates with the bispecific antibody in the tumor. Unbound payload-moeities are rapidly cleared from the circulation.