Since the first ADC drug Mylotarg (gemtuzumab ozogamicin) was approved by the FDA in 2000, a total of 15 ADC drugs have been approved for marketing worldwide to treat hematological malignancies and solid tumors. In addition, more than 400 ADC drugs are in different stages of development. Of the 15 approved ADC drugs, 13 are marketed in the United States, 1 is marketed in China, and 1 is marketed in Japan.
Among the 13 ADCs approved by the FDA, 6 target hematological indications, 7 target solid tumor indications, and 3 target HER2 antigens. With the development of antibody drugs, the advancement of conjugation technology, and the continuous improvement of ADC concepts, the enthusiasm for ADC drug research and development has continued to rise.
In this context, we will briefly review the development stages of ADC drugs, the evolution of ADC Drug Development, and the development trends of next-generation ADC drugs.
ADC is not a new concept. As early as the beginning of the 20th century, Nobel Prize winner in Medicine Paul Ehrlich proposed the concept of ADC and called ADC drugs "magic bombs". But it was not until the 1950s that research on ADC drugs began to improve. In 1958, Mathe first used mouse antibodies coupled with pterygine to treat leukemia. Due to difficulties in immunogenicity and Antibody preparation, ADC drugs stagnated for decades until the introduction of monoclonal antibodies in 1975, and later the emergence of humanized antibodies.
ADC drugs combine the advantages of high specific targeting ability and strong killing effect to achieve precise and efficient killing of cancer cells, and have become one of the hot spots in the development of anti-cancer drugs. In the 1980s, Greg Winter pioneered the humanized monoclonal antibody technology, and the development of ADC drugs made a major breakthrough. However, the technology is still immature. The first ADC drug, Mylotarg, was approved in 2000, but was withdrawn from the market in 2010 due to fatal liver toxicity during use.
Since the FDA approved the first ADC drug Mylotarg in 2000, there are currently 15 ADC drugs approved for hematological malignancies and solid tumors worldwide. Currently, more than 400 ADC drug candidates are in different stages of clinical trials.
Fig. 1 Timeline of important events in ADC drug development and approval. (Fu, et al., 2022)
From the perspective of drug composition and related technical characteristics, the development of ADC drugs can be divided into four generations.
Representative drugs: The first-generation ADC representative drug is Mylotarg, which was the first ADC drug approved by the FDA in 2000 for the treatment of acute myeloid leukemia. However, Mylotarg was voluntarily withdrawn from the market in 2010 due to severe and fatal liver damage and no obvious survival benefit, and was re-listed in 2017.
Drug design: The first-generation ADC drug was an attempt to use anti-mouse leukocyte immunoglobulin in combination with methotrexate to treat leukemia in 1958. The first-generation ADC drugs represented by Mylotarg had high off-target toxicity and low efficacy, and most of them ended in failure.
Disadvantages: The disadvantages of the first-generation ADC drugs are that the antibodies are mouse antibodies, the linkers cannot be cut, and the cytotoxins are insufficient.
This generation of ADC drugs improved mAb technology and carefully selected monoclonal antibodies to improve tumor cell targeting and reduce cross-reactions with healthy cells. More importantly, there was a lack of clinical research on the early use of small molecule drugs, which were then used as toxic loads for Cancer treatment, and more effective small molecules were later discovered.
However, since the second-generation ADC drugs are still coupled using traditional chemical methods, the drug-to-antibody ratio (DAR) is poorly uniform (0-8 or even higher), the linker is unstable, and it is easily cleaved in the blood, causing serious toxic side effects.
Representative drugs: The development of second-generation ADC drugs began with Kadcyla, the first approved ADC drug for breast cancer. The most successful ADC drug in the field of hematological oncology is Adcetris, which focuses on classical Hodgkin's lymphoma and anaplastic large cell lymphoma.
Advantages and disadvantages: The advantages of second-generation ADC drugs are diversified target antigen development, humanized antibodies, and cleavable linker technology. The disadvantages are too low or too high drug loading rate, narrow therapeutic window, and low effectiveness.
Based on the first and second-generation ADC drugs, this generation of ADC drugs uses Site-specific Conjugation technology to produce ADC drugs with uniform DAR values, showing less off-target toxicity and better pharmacokinetic efficiency. And switch to fully humanized antibodies to further reduce immunogenicity.
Representative drugs: Enhertu, Besponsa, Padcev, etc. are representatives, which improve the stability and pharmacokinetics of drugs. The typical representative of the third-generation ADC drugs is Padcev, which is the second ADC drug targeting solid tumors and is suitable for patients who have failed PD-1/PD-L1 antibody treatment.
Advantages and disadvantages: The advantages of the third-generation ADC drugs are small molecule mAb site-specific conjugation technology, development of bispecific antibodies, and eukaryotic RNA splicing inhibitors to enhance specificity. The disadvantages are that the conjugation technology is difficult to reproduce and is insensitive to tubulin Inhibitors.
Representative drugs: Trodelvy, SKB264.
This generation of ADC drugs uses topoisomerase I inhibitors in its payload, mainly camptothecin derivatives such as topotecan, irinotecan and belototecan; in terms of drug design, they are generally designed to be low-toxic and high-toxic. For DAR molecules, the DAR values of two Trop-2-targeting ADC drugs Trodelvy and SKB264 are 7.6 and 7.4, respectively, and the DAR value of DS8201 is 7.8, which can provide more payload to tumor cells and exert therapeutic effects.
Overall, compared with the previous three generations of ADC technology, this generation of ADC technology has made greater progress, but there is still room for further optimization:
From the development of ADC drugs, it can be seen that with the change of technology, the specificity and cytotoxicity of the new generation of ADCs are getting better and better than the previous generations. Of course, there are still certain challenges in the development of ADC drugs. The following will outline the possible development trends of ADC drugs.
Current studies indicate that ADC internalization and intracellular transport pathways have a critical impact on the cytotoxic activity of ADC. Mutated proteins typically have higher levels of ubiquitination and are more susceptible to internalization and degradation than wild-type proteins. This means that if ADCs are used to target the mutant protein, it could lead to significant clinical responses. It is conceivable that targeting ADCs carrying oncogenic mutated proteins, such as certain EGFR mutants, could maximize the tumor specificity of treatment to the level of selective TKIs.
Advances in bispecific antibody technology have brought more possibilities for ADC innovation. These ADC designs can improve antibody internalization and increase tumor specificity. Therapies currently in development have been exploring these possibilities. Bispecific ADCs targeting different sites on the same antigen can improve receptor clustering and lead to rapid internalization of the target. Furthermore, bispecific ADCs dual-targeting HER2 and LAMP-3 demonstrated better lysosomal accumulation and payload delivery in preclinical experiments.
Dual-payload ADCs using two different cytotoxic drugs as payloads to reduce drug resistance. By precisely controlling the ratio of the two drugs, more effective treatments can be achieved by delivering two synergistic payloads into cancer cells. And with the application of payloads with two different mechanisms, the incidence of drug resistance will be greatly reduced. For example, a homogeneous anti-HER2 ADC containing both MMAE and MMAF was designed and exhibited more significant antitumor activity compared with co-administration of the corresponding single payload ADC in a xenograft mouse model.
Another ADC development strategy is to abandon the traditional mAb structure and choose to couple the payload to a smaller molecular weight peptide fragment. The main purpose of these strategies is to reduce the molecular weight of ADCs, thereby improving penetration efficiency and payload delivery to tumor tissues. The current technical challenge for such ADCs is that they can be cleared quickly in the plasma. However, if we can overcome this obstacle, it could potentially treat inaccessible tumors, including those with poor vascular innervation and tumors of the central nervous system.
Traditionally, ADCs require monoclonal antibodies with high internalization capacity in order to deliver their payload into cancer cells. However, mAbs often have difficulty diffusing into solid tumor masses due to antigenic barriers. Therefore, non-internalizing antibodies against ADCs can be developed. It is based on the principle that the payload is directly released outside the cells under reducing conditions in the Tumor Microenvironment, and then diffuses into the cancer cells to cause cell death.
Finally, there are many opportunities for innovation in payload selection.
Currently, a variety of ADC therapies have been successfully developed, benefiting tens of thousands of cancer patients. The approval of 15 ADC drugs and the excellent clinical performance of multiple ADCs have also attracted more people to pay attention to this field, which is very important for this relatively young but highly complex field. With the continuous efforts of researchers in these fields, it is not difficult to imagine that future ADCs will show more surprises in targeted cancer treatment.
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