Evolving ADC…pharma companies explore new DAC platform

Companies are conducting clinical trials for DAC, a technology that links ADC and targeted protein degraders technology

Orum Therapeutics first to start its clinical trial…Pfizer, Merk, and Lily also invest in the field

New forms of technology utilizing the antibody-drug conjugate (ADC) are global trends.

 

One such form is the degrader-antibody conjugate (DAC), a conjugate with the ADC merged with targeted protein degradation (TPD).

 

According to industry sources on the 27th, Biotech companies, including Orum Therapeutics, Nurix Therapeutics, Prelude Therapeutics, and C4 Therapeutics, are developing DAC.

 

Global pharmaceutical companies are investing in major biotech companies due to the potential for commercialization of DAC.

 

ADC is a novel anticancer drug that connects an antibody, which binds to specific antigens on the surface of cancer cells, with a cytotoxic drug linked by a linker.

 

ADCs take advantage of antibodies' selectivity for their targets and the drug's cytotoxic activity to selectively target cancer cells, thereby increasing therapeutic efficacy while minimizing side effects.

 

While Roche's Kadcyla, the first-generation ADC, is only approved for breast cancer, second-generation ADCs are approved for various indications.

 

Enhertu and Trodelvy have been shown to be effective in various solid cancer areas, such as breast cancer, non-small cell lung cancer (NSCLC), and colorectal cancer.

 

Consequently, several companies have tried to link new drugs to ADC forms.

 

Notably, DAC is expected to be safer than ADC since it uses TPD, a low-molecule protein degrader.

 

Despite its high intracellular target specificity and ability to induce decreased protein expression, TPD has low in vivo utilization.

 

Developers are conducting clinical trials to use TPD and ADC for precise target identification.

 

BMS·Merk·Pfizer invest in biotech companies…Orum Therapeutics has started clinical trials

Orum Therapeutics, Nurix Therapeutics, Prelude Therapeutics, C4 Therapeutics, and Firefly Bio are developing DAC.

The first company to start the clinical trials is Orum Therapeutics.

 

Orum Therapeutics is conducting a phase 1 trial of ORM-6151, a candidate product for the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome.

 

ORM-6151 is anti-CD33 antibody-enabled GSPT1 protein inhibitor.

 

Last year, it received approval for Phase 1 clinical trials from the U.S.

 

Food and Drug Administration (FDA).

 

CD33 is known to be expressed in up to 90% of leukemia patients.

 

Orum Therapeutics has an in-house technology for linking ADCs to protein degraders.

 

Bristol Myers Squibb (BMS) successfully acquired a license-in agreement on ORM-6151.

 

The contract size was a maximum of KRW 230 billion, but BMS paid a non-refundable upfront fee of KRW 129.8 billion.

 

BMS highly praised the potential of DAC candidate development with the TPD approach.

 

Global pharmaceutical companies are actively seeking to acquire DAC platform technology.

 

Last year, Seagen (currently, Pfizer) signed a partnership agreement with U.S.

 

biotech company Nurix Therapeutics to develop pan-targeting DAC.

 

Seagen paid an upfront fee of $60 million.

 

The contract size is up to US$3.4 billion (about KRW 4.7 trillion).

 

Nurix Therapeutics has a targeted protein degrader and modulation platform.

 

The company’s pipeline includes an E3 ligase inhibitor that selectively modulates protein levels in cells.

 

Nurix Therapeutics plans to develop new drugs utilizing this pipeline in DAC.

 

DAC mechanism of action.(Source=Nurix Therapeutics)

Merk will co-develop DAC with C4 Therapeutics of the United States.

 

C4 Therapeutics specializes in TPD development and has a TORPEDO (Target Oriented Protein Degrader Optimizer) platform.

 

This platform, a cell-based modality to assess the degradation of disease-causing proteins, can be used to evaluate individual degraders’ efficiency.

 

Lily also invested in Firefly Bio of the United States, engaging in DAC development.

 

Firefly Bio has a proprietary linker technology that can be used in DAC.

 

In a preclinical study analyzing patients with solid cancer and blood cancer, Firefly Bio’s DAC significantly reduced tumor size with a single administration.

 

Prelude Therapeutics, a biotech company in the United States, and Canada’s AbCellera are developing ADC utilizing TPD.

 

In November last year, Prelude Therapeutics signed a partnership agreement with Canadian biotechnology company AbCellera to develop ADCs related to up to five cancer disorders and DACs utilizing TPD.

 

Two companies plan to develop SMARCA degrader DAC that targets five cancer types, including SMARCA4 mutation.