Pioneering
Next-Generation ADCs with Payloads driving
Targeted Protein Homeostasis
Physics-based simulation of
E3 Ligase (CRBN) | Target protein of interest (GSPT1) | Degrader ( SMol006 ) | Water molecules
Targeted Protein Degradation (TPD)
TPD molecules are a class of small molecule drugs that have been developed to leverage the cells normal protein quality control machinery to degrade previously ‘undruggable’ targets for therapeutic benefit. In all cells, proteins that have ceased to function properly are targeted for removal by the ubiquitin-proteasome machinery, via the interaction of these dysfunctional proteins with one of a class of E3 ubiquitin conjugating enzymes.
There are two main types of TPD molecules, molecular glues and heterobifunctional degraders that function by interacting with E3 ligases and driving them to help degrade new target proteins.
Molecular glues bind to the CRBN E3 (or other E3 proteins) and directly drive the recruitment of novel substrate proteins such as IKZF1/3 (as in the case of thalidomide) or GSPT1 (as in the case of SMol006 – our proprietary payload).
Heterobifunctional degraders (also known as PROTACs) utilize an E3 binding moiety coupled to a specific substrate protein binding moiety to engineer the interaction between a desired target protein and the ubiquitin / proteasome machinery.
TPD² ™ Approach
Orum’s proprietary Dual-precision Targeted Protein Degradation (TPD² ™) approach uses antibodies to precisely deliver small molecule targeted protein degrader payloads to cancer cells and for other targeted biological therapies. The TPD² approach has produced our ORM-5029 and ORM-6151 product candidates and various early-stage technologies
TPD² is designed to merge the power of TPD with the precision of ADC technology, while overcoming the limitations of each modality. Whereas TPDs are typically small molecules that indiscriminately enter many cells throughout the body, we covalently attach protein degraders to antibodies to drive localization to specific cells. This is designed to improve upon what we believe are three critical limitations of conventional targeted protein degrader product candidates:
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Our preclinical assays demonstrate the potency of protein degraders can be enhanced by up to one thousand-fold through our antibody-mediated delivery approach
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Antibody-coupled degraders are inactive until they are internalized and released from the antibody. Internalization of these antibodies is dependent on binding to specific cell surface antigens, reducing the exposure of non-targeted cells to the effects of the protein degrader
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Coupling of small molecule protein degraders to antibodies leads to increases in payload half-life and drug exposure
TPD² ™ PROTAb Linker Platform for DACs
Orum has pioneered the discovery and development of DAC(Degrader-Antibody Conjugate) technologies. We are the first to take a DAC into the clinic and have developed a novel and proprietary linker technology that enable us to empower the targeted delivery of a broad spectrum of TPD molecules to potentially improve bioavailability, efficacy, selectivity, and safety.
PROTAb Platform: One of the main challenges in developing targeted protein degraders lies in their limited cell permeability and oral bioavailability, which has precluded many of these degraders from consideration as viable drug candidates. Orum has addressed this issue through an ADC-friendly traceless linker platform which enables the stable conjugation to the glutarimide ring of the cereblon-based degraders (glue or heterobifunctional) to an antibody, without necessitating any modification to the degrader's chemical structure. Upon targeted delivery and intracellular triggering, the linker undergoes rapid hydrolysis, thereby unleashing the active degrader, achieving a seamless and "traceless" release of the payload. PROTAb utilizes a wide array of conditional release triggers, including those incorporating a water-solubilizing moiety into the adapter. This significantly enhances the conjugatability and drug-like characteristics of the resulting PROTAb molecules.
PROTAb enables a universe of degraders to be applied as a DAC for a breadth of indications
Tumor Immunology
Immune checkpoint inhibitors (ICI) marked a significant milestone in the landscape of cancer immunotherapy, demonstrating the power of restoring T cell function in fighting cancer cells. Despite this, there are a significant number of patients who do not respond to ICI therapies.
More recently, Casitas B lymphoma-b (Cbl-b) has been identified as an E3 ubiquitin ligase which fosters an immunosuppressive milieu in the tumor microenvironment. Inhibition of Cbl-b via genetic or small-molecule targeting, has been shown to reverse immunosuppression, activate cytotoxic T cell responses, and cause tumor regression. The systemic loss of Cbl-b, however, is tied to toxicities associated with immune system activation, such as cytokine storm and other severe autoimmune reactions.
Cbl-b - A Compelling New Target in IO
E3 ligase, ubiquitinates and degrades PI3K and other signaling proteins for regulation of T cell activation
Many inhibitory signals in T cells - including PD-1 and CTLA-4 signaling - feed into Cbl-b pathway
Cbl-b inhibition also induces resistance towards negative cues from the environment, such as soluble TGF-β or Treg
Cbl-b-knockout effector T cells are resistant to TGF-β or Tregs-induced Th17 differentiation
Absence of Cbl-b suppresses the generation of inducible Treg by TGF-β
TPS² ™ Approach
Numerous diseases are instigated by proteins undergoing aberrant ubiquitination and subsequent degradation, and targeted stabilization of these proteins may lead to transformative therapeutics. Orum’s proprietary Dual-precision Targeted Protein Stabilization (TPS²) approach combines novel payloads with the precise cell delivery mechanism of antibodies to increase the levels of intracellular target proteins in a cell-type-specific manner for oncology and immuno-oncology.
Leveraging the TPS² approach, we are enhancing anti-tumor immune response by directing Cbl-b inhibitors specifically to exhausted T cells via antibody delivery. By enabling the localization of Cbl-b inhibitors within the tumor microenvironment while simultaneously blocking the immune checkpoint signal, this dual-precision approach aims to broaden the horizon of cancer immunotherapies.
Orum’s Discovery Engine
Integrating key research expertise to create next-generation ADC’s regulating protein homeostasis.
Publications
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ORM-5029: A First-in-Class, Tumor-Targeted, Targeted Protein Degradation Therapy for HER2-Positive Breast Cancer
( AACR 2022 )
Development of RNAscope Multiplex-Based Assay for Exploratory Pharmacodynamic Biomarkers Assessment in Breast Cancer Patients from Phase I Clinical Trial Of ORM-5029, a Potent GSPT1 Degrader
( AACR 2023 )
A Phase 1, First-in-human, Open Label, Escalation and Expansion Study of ORM-5029, A Highly Potent GSPT1 Degrader Targeting HER2, in Patients with HER2-expressing Advanced Solid Tumors (NCT05511844)
( ASCO 2023 )
ORM-5029: Discovery of an antibody drug conjugate with first-in-class molecular glue degrader warhead for treatment of HER2-positive breast cancer
( ACS 2023 )
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Novel antibody-enabled Dual-precision Targeted Protein Stabilization (TPS²) that augments anti-tumor immune response by targeting Cbl-b inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1
( AACR 2023 )