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.

Infographic comparing targeted protein degraders with current and next-gen approaches. "Current Approaches" show molecular glues and PROTACs affecting all or specific tissues with risks of off-target toxicity. "Orum's Next Gen Approach" highlights cell-specific targeting, delivering degraders to disease-causing cells like tumors for more precision.

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:

  • Our preclinical assays demonstrate the potency of protein degraders can be enhanced by up to one thousand-fold through our antibody-mediated delivery approach

  • 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

  • Coupling of small molecule protein degraders to antibodies leads to increases in payload half-life and drug exposure

Illustration of Degrader-antibody-conjugate mechanism in tumor cell. Includes labeled steps
A graphic outlining four steps in a cancer treatment process. Step 1: Antibody-enabled molecular glues enter the cell targeting tumor antigens. Step 2: Molecular glues bind to the target protein and Cereblon (E3 Ligase). Step 3: The proteasome degrades the ubiquitin-tagged target. Step 4: Continued degradation of the target protein leads to cancer cell death.

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.

Diagram showing a process of conjugate degraders on the PROTAb linker platform

PROTAb enables a universe of degraders to be applied as a DAC for a breadth of indications

Diagram showing intracellular degrader targets and surface antibody targets with oncology and non-oncology categories. It includes target lists and a section labeled 'TPD² Indications' detailing medical conditions related to oncology and non-oncology.

Publications

  • ORM-6151: A First-in-Class, Anti-CD33 Antibody-Enabled GSPT1 Degrader for AML
    ( ASH 2022 | AACR 2023 )

  • 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 )

  • PROTAb Platform: An Innovative Universal Linker for DACs with Cereblon-Based Degraders

    ( ADC Linker & Conjugation Summit 2024 )