One of the hottest new cancer treatments are Antibody-Drug Conjugates (ADCs). 15 ADCs are approved so far and over 210 are in clinical trials. The ADC drug development has entered a phase of proliferation over the past couple of years on several target (HER2, EGFR, Trop2, CLDN18.2, Nectin-4), with high efficacy and safety. Drug combination therapy and bispecific ADCs have been incredibly successful, providing patients with more treatment options. As technology keeps advancing and improving, the application prospects of ADC therapy in the field of cancer treatment are very broad.
ADC is a new biological drug that links Monoclonal Antibodies and cytotoxic agents via chemical linkers. At the heart of its idea is to combine the specific targeting of antibodies with the powerful killing effect of cytotoxic drugs. After ADC reaches the bloodstream, its antibody component can identify and attach to the target antigen on the surface of the tumour cell to create an ADC-target antigen complex, then the ADC is taken into the cell through the cell’s endocytosis. Once inside the cell, the linker is cleaved in a specific intracellular context, released the cytotoxic compound, thereby killing the tumor cells. This design should enable targeted attack on cancer cells, reduce damage to normal cells, and increase the efficacy and safety of cancer treatment.
ADC drug development requires comprehensive consideration of multiple key factors. The first is target selection, focusing on its specific high expression in tumor cells and its correlation with tumor biological processes. In terms of antibody design, it is necessary to ensure low immunogenicity, strong specificity, high internalization efficiency and long half-life to achieve effective delivery of ADCs in the body. The linker design should take into account both stability and cleavability, as well as chemical compatibility. At the same time, it should avoid causing aggregation of ADCs, prevent premature release of payload in the blood, and accurately release active drugs at the target location. Cytotoxic agents must be physiologically stable and possess functional groups that could bind to antibodies. Apart from the selection of antibodies, Linkers and cytotoxic agents, the way small molecules are attached to antibodies is an important part of the successful construction of ADCs. Choosing the right coupling scheme can significantly affect ADC stability and performance.
Fig. 1 Mechanism of action of ADC drugs. (Fu, et al., 2022)
The concept of ADC was first proposed by German medical scientist and Nobel Prize winner Paul Ehrlich in the early 20th century. Yet it wasn’t until monoclonal antibodies developed in the 1970s, combined with the evolution of protein recombinant engineering technology, that ADC research slowly became a favored Antibody Drug development area. Mylotarg, a drug by Wyeth Pharmaceuticals, was accelerated by the US FDA in 2000 for use in CD33-positive acute myeloid leukemia (AML) patients. It was the first ADC drug to ever be sold in the world. But it was fatally toxic in clinical trials, so the drug was taken off the market in 2010 and approved again in 2017 with modifications in specifications and clinical data added. Since then, the ADC field has experienced a long period of silence.
In the eight years during this time, only four products were approved, Adcetris, Kadcyla, Besponsa and Lumoxiti, and the whole ADC industry matured in a slow pace. 2019 is the year when ADC has reached its milestone. And three ADCs — Polivy, Padcev, and Enhertu — were approved this year. Among them, Enhertu is regarded by the industry as the biggest catalyst for the sharp recovery in the ADC field. Enhertu significantly improved the survival and remission levels of breast cancer patients, and because Enhertu has significant activity against both HER2-positive and low-expression tumors, the industry has paid more attention to the "bystander effect" of ADCs on malignant cells other than the target. After 2019, the ADC track ushered in the intensive approval of products such as Trodelvy, Blenrep, and Zynlonta, and the market size also grew exponentially.
However, the ADC drug market also faces some challenges, such as the termination of cooperation between enterprises and potential drug resistance issues. But overall, its growth trend is obvious, the market potential is huge, and its development in Cancer treatment and related fields is worth looking forward to.
With the rapid approval of oncology-oriented ADC drugs, the future may continue to develop along the existing path, including the development of more ADC drugs carrying topoisomerase I inhibitor (TOPO1i), microtubule inhibitors, and DNA damaging agents, testing of approved ADC drugs in unexplored indications, and the evaluation of ADC combinations with immune checkpoint inhibitors and other anti-cancer drugs. At the same time, in order to realize the dream of "magic bullet", further innovative design of ADC drugs is needed. This includes fine-tuning the molecular characteristics of ADCs, such as by selecting cytotoxic molecules with different potencies and mechanisms of action, adjusting drug-to-antibody ratios, and linking technologies, to increase drug activity and reduce toxicity.
In addition, the performance of ADC drugs can also be optimized by combining other drugs or adopting new dosing strategies. Meanwhile, more radical innovation ideas include replacing one or more components of an ADC, such as developing bispecific or multispecific ADCs, introducing peptide masks, modifying the binding properties of antibodies, and replacing antibodies with smaller molecules. While ADC drugs have come a long way, our understanding of their mechanisms of action remains limited. The action mechanism of ADC drugs in the body – its uptake, distribution, metabolism and elimination, as well as the interaction between drug, target and other biomolecules – will require further comprehensive studies in the future. This will allow us to design and optimize ADC drugs for improved therapeutic performance and safety.
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