In recent years, antibody-drug conjugates (ADCs) have been widely sought after due to their excellent clinical performance and market returns. ADC drugs are composed of three parts: antibody, effector molecule (Payload, usually cytotoxic agent) and linker. Compared with traditional drugs, ADC drugs have obvious advantages in improving targeting and reducing side effects.
1. Global ADC listing and research status
As of April 2, 2021, there are 432 ADC drugs under development worldwide. Most of them are in the pre-clinical stage, and 108 products are in the clinical stage. Since the first ADC product Mylotarg (gemtuzumab ozogamicin) was launched in 2000, a total of 11 ADC products have been approved for launch worldwide.
2. Treatment field and target
In the field of treatment, the main research and development direction of ADC drugs is concentrated in the field of anti-tumor. There are few competitors in the rest of the treatment field, but there are many potential products. ABBV-3373, which is being developed by AbbVie, is an ADC drug composed of adalimumab and glucocorticoid receptor modulator (GRM) for the potential treatment of rheumatoid arthritis (RA). According to its Phase III experimental data released in June 2020, compared with adalimumab, ABBV-3373 could bring a more significant improvement in the DAS28 CRP score in the 12th week, and its safety is similar to the known safety of adalimumab. In terms of target selection, it is similar to the drugs already on the market. At present, the target distribution of products under research in the world is relatively scattered, and only Her2, EGFR, CD-19, TROP-2 and other targets competing fiercely.
3. Photoimmune ADC
In terms of effector molecules, ADC drugs currently on the market and under development mostly choose Auristatins (such as MMAE, MMAF), maytansine (such as DM1, DM4), calicheamicin and other cytotoxins as their effector molecules. There are also pharmaceutical companies that have begun to carry out research and development of “unconventional” effectors. Among them, in September 2020, the world's first photoimmunotherapy ADC drug cetuximab sarotalocan developed by Rakuten Medical was approved for marketing, which opened the way for the subsequent development of photoimmune ADC drugs.
Near-infrared photoimmunotherapy (NIR-PIT) is a molecularly targeted light therapy for cancer. The therapy is mainly composed of monoclonal antibodies (mAb) directed against the antigen expressed on the surface of cancer cells and a near-infrared light-absorbing dye (IR700) that has cell-killing properties.
Traditional immunotherapies, such as immune-activating cytokine therapy, checkpoint inhibition, engineered T-cells, etc., do not directly destroy cancer cells, but completely depend on activating the immune system. NIR-PIT can selectively destroy cancer cells while activating the body's immune response.
After the antibody drug binds to the tumor surface antigen, under near-infrared light stimulation, IR700 undergoes a light-induced ligand release reaction, releasing hydrophilic side chains, resulting in a significant increase in the hydrophobicity of the remaining part. It then destroys the cell membrane and triggers rapid and highly selective immunogenic cell death (ICD) targeted to cancer cells. While directly killing cancer cells, ICD induced by NIR-PIT can cause immature dendritic cells adjacent to dead cancer cells to mature rapidly, initiate host anti-cancer immune response, promote the re-formation of CD8-positive T cells against antigens released by dead cancer cells, and further magnify the therapeutic effect of NIR-PIT.
Cetuximab sarotalocan is the first product of photoimmune ADC, which is formed by linking water-soluble silicon phthalocyanine derivative IRDye700DX and cetuximab. After 24 hours of administration, the drug specifically aggregated on the surface of EGFR-positive tumor cells, and then irradiates the tumor site with 690nm wavelength near-infrared light to induce Cetuximab sarotalocan to kill cancer cells and activate the immune response. The phase III clinical trial (LUZERA-301) of the drug for recurrent head and neck cancer was completed in December 2018.
In addition to Cetuximab sarotalocan, there are a total of five immunological ADC projects under research worldwide, all of which are in the pre-clinical or drug discovery stage, and all use IR700 as their effector molecule.
At present, the broad market prospects of ADC drugs have set off an upsurge in the research and development of related products worldwide. Although the number of products on the market is small, the products in the research phase have already experienced a certain degree of target crowding and duplication of effector molecules. As the “unpopular track” in the ADC field, photoimmune ADCs still need time to test their clinical and market prospects. However, the development of new targets and new light-activated effect molecules based on related principles may become a new breakthrough point in the ADC track.
