Orum Therapeutics Advances Next-Generation ADCs by Integrating Targeted Protein Degradation with Antibody Conjugation

With the explosive growth in the number of clinical trials and the rise of next-generation drugs, many pharmaceutical companies are adding antibody-drug conjugate (ADC) therapies to their product portfolios.

The first clinical trial involving an antibody-drug conjugate (ADC) was approved in 2000 for the treatment of acute myeloid leukemia (AML). In 2019, Enhertu received its initial approval for breast cancer, non-small cell lung cancer, and gastric cancer, marking a milestone in the development of ADCs.

Sung Joo Lee, CEO of Orum Therapeutics, pointed out that the success of Enhertu is driving the development of next-generation ADCs. Meanwhile, next-generation ADCs must also overcome the challenges faced by current ADC drugs.

For instance, how to address the challenges posed by toxicity and the tumor microenvironment. Nathan Tumey, Associate Professor at the School of Pharmacy and Pharmaceutical Sciences at Binghamton University, noted that many questions remain regarding the drivers of ADC toxicity. Previously, premature payload release was considered the primary cause, but he stated that this is no longer regarded as the main or sole issue. “Even highly stable ADCs exhibit toxicity issues; understanding the molecular basis of ADC toxicity will represent an important step forward,” said Tumey.

Another challenge facing ADCs is the limited number of tumor-specific antigens in solid tumors. Therefore, next-generation ADCs will emerge in more innovative and iterative forms. Tumey stated,Next-generation ADCs differ from currently marketed ADCs in that they incorporate novel features, including site-specific conjugation, new payload mechanisms, and novel antibody formats.These features are typically designed to broaden the therapeutic window or advance new therapeutic indications.

Among them, the South Korean pharmaceutical company Orum Therapeutics is dedicated to developing next-generation antibody-drug conjugate (ADC) therapies. By focusing on the integration of protein degraders with ADCs, the company has built a broad and highly differentiated pipeline of candidate products, offering patients more therapeutic options and approaches.

Orum Therapeutics, established in August 2016 and headquartered in Daejeon, South Korea, is dedicated to developing novel therapeutic antibodies (“Cure Antibodies”) and leveraging its proprietary Oromab platform to explore new treatments for cancer and rare diseases. Orum aims to inhibit gene mutations, such as those in the RAS gene, through antibody-based therapeutics. Research has shown that RAS gene mutations are closely associated with the development of lung cancer, pancreatic cancer, and colorectal cancer.

Orum boasts a professional antibody R&D team. The company’s founder and CEO, Sung Joo Lee, previously worked at the multinational pharmaceutical company Sanofi, and before that, at the LG Life Sciences Research Institute. Sung Joo Lee is dedicated to researching therapeutic solutions for various diseases, including hepatitis B, hepatocellular carcinoma (HCC), diabetes, and Alzheimer’s disease (AD). Additionally, Orum’s Chief Scientific Officer, Peter Park, has over 17 years of scientific research experience in targeted oncology therapies. Peter was also one of the developers of isatuximab, a treatment for multiple myeloma.

Orum Therapeutics aims to leverage its proprietary platform to develop novel therapeutics for cancer and immune diseases, expand the range of drug targets, and meaningfully enhance drug potency and tolerability, thereby improving the therapeutic window.Its goal is to combine emerging protein degraders with antibodies, namely, to develop antibody-degrader conjugates, thereby generating a broad and highly differentiated portfolio of candidate products.

To achieve this goal, Orum has developed the Oromab platform, which is used to develop novel therapeutic antibodies targeting cytosolic binding proteins. These antibodies recognize cell-specific receptors and enter the cytosol via receptor-mediated endocytosis. As a result, therapeutic antibodies developed using the Oromab platform can be activated within the cytosol to target and degrade pathogenic cytosolic proteins. Although this represents a novel modality of drug action, manufacturing concerns are unfounded. Specific cell-penetrating antibodies in their full-length IgG format exhibit pharmacokinetic profiles consistent with those of IgG monoclonal antibodies (mAbs), thereby enabling large-scale production using conventional mAb manufacturing technologies.

Leveraging the Oromab platform technology, Orum is exploring multiple therapeutic avenues, including inhibiting RAS genes and oncogenic drivers, delivering oligonucleotide enzymes for the treatment of cancer and rare diseases, and targeting disease-causing proteins for degradation.

Cutting-edge drug discovery concepts and an executable, implementation-ready technology platform have attracted a series of financing rounds for Orum Therapeutics:

• In June 2017, Orum completed an $8 million Series A financing round led by Solidus Investment and others;

• On July 18, 2019, Orum announced the completion of a $30 million Series B financing round. Investors included IMM Investment, Smilegate Investment, KTB Network, Stassets Investment, InterVest, KB Investment, and Solidus Investment.

• In June 2021, Orum completed an $84 million Series B financing round, comprising the previously announced $30 million and a newly raised $54 million led by IMM Investment, with participation from new investors (including KDB Investment and Atinum) and existing investors (such as Intervest and KB Investment). The proceeds will be used to advance the company’s lead therapeutic candidate into clinical trials, explore other payload chemistries, and develop additional payloads targeting the ubiquitin pathway.

To combine protein degraders (TPD) with ADCs, Orum has pioneered a proprietary technological approach—Dual-precision Targeted Protein Degradation (TPD²™). Currently, many targeted protein degraders under investigation are typically small molecules that enter numerous cells throughout the body indiscriminately,The TPD² approach aims to drive localization to specific cells by covalently attaching protein degraders to antibodies, thereby enabling the precise antibody-mediated delivery of small-molecule targeted protein degradation payloads to cancer cells and other targets.Its aim is to combine the potent capabilities of TPD with the precision of ADC technology, while overcoming the limitations inherent to each modality.

Methods based solely on protein degraders and ADCs are insufficient. Orum has further innovated on its technology platform to developAntibody neoDegrader Conjugate (AnDC) Technology Platform. This platform develops payloads based on novel targeted protein degraders, ensuring their integration with the precise tumor cell delivery mechanism of antibodies to generate innovative conjugate drugs. Under this platform, Orum has developed a novel ADC payload called neoDegraders. neoDegraders can specifically degrade target proteins within cancer cells via E3 ubiquitin ligases. When conjugated to an antibody, they are designed for specific delivery to cancer cells, where they degrade intracellular target proteins to kill tumor cells.

Peter Park, Chief Scientific Officer at Orum Therapeutics, stated: “Advances in ADC therapies have been hindered by the lack of diversity in payloads with novel mechanisms of action that inhibit tumor cell growth, while protein degraders lack tissue specificity. AnDC combines the advantages of targeted protein degraders and ADCs, while overcoming the limitations of each approach. Orum has developed a unique portfolio of payloads capable of targeting intracellular proteins for degradation, which holds the potential to catalyze tumor-killing effects and improve cancer treatment.”

Integrating TPD² with the Oromab platform and AnDC,Orum Therapeutics has developed its core pipeline candidates, ORM-5029 for the treatment of solid tumors and ORM-6151 for the treatment of hematologic cancers.Each program utilizes a distinct antibody-drug conjugate to specifically deliver Orum’s neoDegrader to tumor cells.

Orum’s ORM-5029 is a proprietary GSPT1 degrader conjugated to the HER2-targeting antibody pertuzumab, currently in Phase 1 clinical trials; an IND application for ORM-6151 has been submitted for the treatment of acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes.

Orum Therapeutics has also attracted collaboration offers from MNCs.2In November 2023, Orum Therapeutics announced that it had entered into a definitive agreement with Bristol Myers Squibb (BMS), under which BMS will acquire Orum’s investigational asset ORM-6151—a first-in-class anti-CD33 antibody-linked GSPT1 degrader.

Under the terms of this transaction, BMS will pay Orum an upfront payment of $100 million, along with milestone payments totaling $180 million. Preclinical studies demonstrated that ORM-6151 exhibits potent in vitro cytotoxic activity across all primary, non-passaged AML cells, showing superior potency compared to typical CD33-targeting ADCs (MYLOTARG) or GSPT1 degraders (CC90009).

Currently, the field of antibody degrader conjugates is still in its infancy, but various such entities have been developed. The validated drugs to date have demonstrated meaningful in vitro and/or in vivo biological activity; however, further clinical data are required for confirmation. We look forward to more positive updates from Orum Therapeutics.