In recent years, antibody-drug conjugates (ADCs) have been widely sought after for their excellent clinical performance and market return. And maintained development with higher enthusiasm in range of globe. ADC drugs are composed of three parts: antibody, effector molecule (Payload, usually cytotoxic agent), and ADC 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 in progress worldwide. Most of them are in the pre-clinical stage, with 108 products in the clinical stage.
Stage situation of ADC drugs in global progress
Since the launch of the first ADC product, Mylotarg (Gemtuzumab ozogamicin) in 2000, there are currently 11 ADC products approved worldwide.
2.Therapeutic field and target
In the field of therapy, the main research and development direction of ADC drugs is concentrated in anti-tumor.
There are few competitors in the rest of the therapeutic field, but there is no shortage of major potential products. ABBV-3373 under development by AbbVie, which is adalimumab and a glucocorticoid receptor modulator (GRM) formed ADC drug for the potential treatment of rheumatoid arthritis (RA). According to its Phase IIa experimental data released in June 2020, ABBV-3373 can bring a more significant improvement in DAS28 CRP score at the 12th week than adalimumab. Its safety is comparable to the known safety of adalimumab Sexual similarity.
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, with only Her2, EGFR, CD-19, TROP-2, and other targets competing fiercely.
The status of ADC drug targets in global progress
3.Photoimmune ADC
On the effector molecules side, ADC drugs currently on the market and under development mostly choose auristatin (MMAE, MMAF), maytansine ( DM1, DM4), calicheamicin, and other cytotoxins. Some pharmaceutical companies have also begun to carry out development work on “unconventional” effectors. In September 2020, Cetuximab sarotalocan, the world’s first photoimmunotherapy ADC drug developed by Rakuten Medical, was approved for marketing, paving the way for subsequent photoimmunotherapy ADC drug development.
Near-infrared photoimmunotherapy (NIR-PIT) is a molecular targeted light therapy for cancer. The therapy consists of a monoclonal antibody (mAb) that targets antigens expressed on the surface of cancer cells and a cell-killing near-infrared light-absorbing dye (IR700).
Traditional immunotherapy, such as immune-activating cytokine therapy, checkpoint inhibition, engineered Tcells, etc., does not directly destroy cancer cells, but completely depends on the activation immune system. NIR-PIT can selectively destroy cancer cells while activating the body’s immune response.
NIR-PIT-induced immunogenic cell death
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.
In addition to directly killing cancer cells, NIR-PIT induced ICD can lead to rapid maturation of immature dendritic cells of dying cancer cells, initiate host anti-cancer immune response, and promote the re-formation of CD8-positive T cells against antigens released by dying cancer cells, further amplifying the therapeutic effect of NIR-PIT.
IR700 chemical reaction principle and schematic diagram of coupling protein changes
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 aggregates on the surface of EGFR-positive tumor cells. Then use 690nm wavelength near-infrared light to illuminate the tumor site, induce cetuximab sarotalocan to kill the cancer cells, and activate the immune response.
At present, the phase I/IIa clinical trial (NCT02422979) of the drug for recurrent head and neck cancer has been completed, and the phase III clinical trial (LUZERA-301) has been launched in December 2018.
Cetuximab sarotalocan principle of action
In addition to Cetuximab sarotalocan, there are a total of five immunological ADC projects under development worldwide, all of which are in the preclinical or drug discovery stage, and all use IR700 as their effector molecule.
At present, the broad market prospect of ADC drugs has set off a global upsurge in the research and development of related products. Although the number of marketed products is relatively small, the products in the research stage have appeared some phenomenon of target crowding and effector molecule duplication. As a “minority research” in the field of ADC, photoimmune ADC’s clinical and market prospects still need to undergo the test of time. However, the development of new targets based on relevant principles and new light-activating effector molecules may become a new breakthrough point of the ADC track.
Reference
1. Antibody-Drug Conjugates: The Last Decade.Pharmaceuticals (Basel)
2. Near-Infrared Photoimmunotherapy of Cancer. Acc. Chem.Res.
Related Readings:
- Analysis of Multiple Factors Influencing ADC Pharmacokinetics
- What is BCN：A Versatile Bioconjugation Tool
- Challenges in Antibody-Drug Conjugate (ADC) Development
- ADC: All You Need to Know About Targeting, Termination, Optimization, and Phase II/III Clinical Trials
- XDC | Various New Drug Conjugates, In Addition to ADC, There Are More Choices.