The Rising Popularity of Antibody-Drug Conjugates, with Challenges

by Andrii Buvailo, PhD          Biopharma insight

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Topics: Novel Therapeutics   
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In the current climate of global economic uncertainty, one area of pharmaceutical development is bucking the trend with a significant surge in activity: the field of antibody-drug conjugates (ADCs). This class of drugs is gaining increasing interest from major pharmaceutical companies, as evidenced by a series of high-profile deals and partnerships.

How does an antibody-drug conjugate work?

An antibody-drug conjugate (ADC) works as a targeted cancer therapy by combining the specific targeting capabilities of monoclonal antibodies with the potent cell-killing effects of cytotoxic drugs. Here's how it functions:

Firstly, the monoclonal antibody component of an ADC is designed to recognize and bind to a specific antigen, typically found on the surface of cancer cells. This ensures that the ADC selectively targets cancer cells while sparing healthy cells.

Once the ADC binds to the cancer cell via the antigen, the entire complex is internalized into the cell. This is a crucial step, as it brings the cytotoxic drug into close proximity with the cancer cell.

Inside the cell, the ADC is transported to a cellular compartment called the lysosome. Here, the chemical linker connecting the antibody to the cytotoxic payload is broken down. This process releases the cytotoxic drug inside the cancer cell.

Finally, the released drug exerts its cell-killing effects, typically by interfering with vital cellular processes such as DNA replication, ultimately leading to the death of the cancer cell.

Recent advancements in ADC technology have focused on improving two key aspects: the drug-to-antibody ratio (DAR) and site-specific conjugation. By precisely controlling the DAR, researchers can optimize the therapeutic index of the ADC, balancing efficacy with safety. Additionally, site-specific conjugation, often achieved by introducing unnatural amino acids into the antibody, allows for a more uniform and predictable ADC product, which can improve its effectiveness and reduce side effects.

Mounting Investments and Collaborations

In stark contrast to the general slowdown in dealmaking, marked by higher interest rates and geopolitical tensions, the ADC sector is witnessing a flurry of activity. Notably, Pfizer has acquired Seagen for $43 billion, a move followed by Seagen's collaboration with Nurix Therapeutics. Other pharmaceutical giants like Amgen, AstraZeneca, and Merck have also invested heavily in ADCs, with over $60 billion worth of licensing deals signed in the past five years. 

GSK has just entered exclusive license agreement with China-based Hansoh for HS-20093, a B7-H3 targeted antibody-drug conjugate (ADC) utilising a clinically validated topoisomerase inhibitor (TOPOi) payload. Under the agreement, GSK will obtain exclusive worldwide rights (excluding China’s mainland, Hong Kong, Macau, and Taiwan) to progress the clinical development and commercialization of HS-20093.

This year has seen more than 20 deals involving ADCs, surpassing the number of deals in other emerging cancer drug categories.

The Growing Appeal of Antibody-Drug Conjugates

ADCs, first approved in 2000 for certain types of leukemia, function as targeted cancer treatments. They consist of an antibody that specifically targets cancer cells and is linked to a cytotoxic drug. This targeted approach allows higher drug doses with reduced impact on healthy tissues, presenting a significant advantage over traditional chemotherapy.

The increasing interest in ADCs is partly due to their proven clinical efficacy. A notable example is Enhertu, an ADC developed by AstraZeneca and Daiichi Sankyo, which has shown promising results in treating breast and lung cancer. This success, along with the approval of a dozen other ADCs for various cancers, has fueled both clinical and commercial confidence in this drug class.

Degrader-antibody conjugates

In a recent move in the biotechnology sector, C4 Therapeutics, Inc. (C4T) has announced a collaboration with pharmaceutical giant Merck (MRK). This partnership is centered on the development of degrader-antibody conjugates (DACs), focusing on a key oncology target.

DACs represent an innovative approach in cancer treatment, designed to selectively neutralize disease-causing proteins. This emerging modality combines C4T's advanced protein degradation technology with Merck's expertise in biological chemistry, marking a pivotal step in targeted cancer therapies.

Under the terms of the agreement, C4T receives an initial $10 million from Merck, with the potential to earn up to $600 million in milestone payments, along with royalties on future net sales. Merck will lead the development phases, encompassing preclinical and clinical studies, and will oversee the commercialization of any successful therapies.

The deal also includes an option for Merck to extend the collaboration to three additional targets, which could result in nearly $2.5 billion in total payments for C4T. This agreement is a strategic boon for C4T, providing crucial funding to support its research and development pipeline.

Future Prospects and Challenges

More than 140 ADCs are currently undergoing clinical trials, with companies like Bristol-Myers Squibb and Sanofi conducting late-stage tests. AstraZeneca and Merck are expanding their ADC operations into China, leveraging the country's more lenient regulations for early-stage trials to expedite drug development.

The commercial success of ADCs is also notable. Sales of Enhertu reached $1.2 billion in 2022, with other ADCs like Trodelvy and Kadcyla also reporting significant revenue. The overall market for ADCs is projected to reach nearly $30 billion by 2028.

With all the excitement, the ADCs market is facing unique challenges. The complexity of manufacturing these drugs and the uncertainty of their performance in combination with other treatments like immunotherapies are concerns. Additionally, geopolitical tensions could impact collaborations with Chinese partners.

Also, Sanofi has recently halted the development of tusamitamab ravtansine, an antibody-drug conjugate (ADC), for non-small cell lung cancer (NSCLC) after it failed to meet the primary endpoint in the Phase III CARMEN-LC03 trial. The trial compared tusamitamab ravtansine with chemotherapy docetaxel in NSCLC patients, focusing on tumors with high levels of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5); however, it did not achieve progression-free survival (PFS) despite an improved overall survival trend. 

Despite this setback, Sanofi remains committed to exploring tusamitamab-based ADCs and CEACAM5 in other cancer types, continuing its engagement in the ADC field through partnerships and collaborations, including a significant agreement with Seagen for developing and commercializing cancer treatment ADCs.

As a general trend, the enthusiasm for ADCs in the pharmaceutical industry is evident. This "global arms race" in cancer treatment is a significant development in the quest to provide more effective therapies for one of the world's most challenging diseases.

Topics: Novel Therapeutics   

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