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Orum Therapeutics is developing a new class of therapeutic antibodies targeting cytosolic proteins for unmet medical needs in cancer and rare diseases. Orum leverages its unique cell-specific, cell-penetrating antibody platform, called OromabTM to inhibit cytosolic drug targets, previously undruggable by small molecules or current antibody therapeutics. In contrast to other approaches, Orum’s antibody platform can intracellularly deliver an active antibody therapeutic or payload, is easily adaptable to target different cell types and intracellular proteins, and does not require chemical modification.

Using the Oromab platform, Orum builds cell-penetrating antibodies that bind cell-specific receptors, pass through the cell membrane, and are internalized through receptor-mediated endocytosis. With Orum’s proprietary design, these antibodies do not reach the lysosome, but escape the early endosome into the cytosol. Once in the cytosol, the antibodies can be therapeutically activated and directly target disease-causing cytosolic proteins or deliver payloads. With the Oromab platform, Orum is exploring several therapeutic avenues: 1) inhibiting Ras and tumor-specific intracellular oncogenic drivers, 2) delivery of oligonucleotides or enzymes for cancer and rare diseases, and 3) targeted degradation of disease proteins.

Cell Penetrating Antibody
Due to their large sizes and hydrophilicity, conventional antibodies cannot cross cellular and subcellular membranes in living cells. Although they can be internalized through receptor-mediated endocytosis, they are unable to escape intermediate early or late endosomes, and will ultimately undergo degradation in lysosomes.

Outcomes Following Endocytosis of Antibody

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Orum’s cell-penetrating antibody (Oromab) is a full-length IgG incorporated with a cytosol-penetrating VL that can reach the cytosol of living cells by recognizing cell surface receptors and undergoing receptor-mediated endocytosis. In the early endosome, the weakly acidic conditions induces an interaction between the antibody and the endosomal membrane, subsequently transporting the Oromab into the cytosol without degradation.

Intact IgG-format Oromab can be produced in large-scale using conventional mAb production techniques, and it maintains the many desirable features of conventional IgG mAbs, like pharmacokinetics. Moreover, Oromabs can be further engineered to target cytosolic proteins by incorporating intracellular target-recognizing VH into the heavy chain of the antibody.

Features of Orum’s Cell-penetrating Antibody Technology

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With their unique ability to escape the endosome, Oromabs are a new class of antibodies that can be internalized into the cytosol of living cells without affecting cell viability or proliferation.

 

 

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Targeting Oncogenic Drivers
Our Ras Program

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Lack of binding pocket, tight binding of GTP, and subcellular location make discovery of conventional small molecules or biotherapeutics difficult.

Ras proteins are small GTPases—inactive when bound to GDP and active when bound to GTP—that play an important role in cell proliferation and survival. In many human cancers, oncogenic mutations in the RAS genes result in overactive Ras proteins, which can lead to abnormal cell proliferation and cancer.

Although the recent development of KRAS G12C inhibitors appear promising, Ras has mostly been undruggable due to the lack of a pocket for high-affinity binding in the absence of covalent interaction.

Orum’s Ras Antibody inhibits Ras-Effector interaction

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Our technology presents a new approach to targeting Ras. Through internalization into the cytosol of living cells, Oromab directly targets intracellularly activated GTP-bound forms of oncogenic Ras mutants.

Other Oncogenic Driver Programs

Other programs against tumor-specific oncogenic drivers are currently in antibody discovery stages.

 

 

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Intracellular Delivery of Therapeutic Cargoes

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Since antibodies have been developed as a targeting moiety, scientists have been trying to use antibodies to deliver cargos such as drugs, toxins, enzymes and oligos. With the recent approval of antibody-drug conjugates, there have been tremendous efforts to improve efficacy and the safety of conjugates by target selection, the use of various linkers, changing drug-to-antibody ratio (DAR) and different sites of conjugation. Antibody or ADC binds to the surface target is internalized and trafficked through endosomes and ultimately to lysosome. The efficiency of endosome escape into cytosol before the delivery to lysosome for degradation is extremely low. Hence, the difficulty of delivery of any antibody-conjugated cargos to cytosol.  

With the increased efficiency of antibody delivery to cytosol, Oromab conjugates carrying cargo, such as oligonucleotides or enzymes have the potential to deliver enough cargo to the target cells to have pharmacological and ultimately therapeutic effects. We are currently exploring delivery of oligonucleotides and enzymes for the use in oncology and rare diseases.   

Targeted Protein Degradation
The majority of disease-causing intracellular proteins are not amenable to modulation by traditional therapeutic modalities.  We are currently exploring targeted degradation of intracellular diseased proteins using cell-penetrating antibody platform.

 

 

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