ADC technology continues to advance, and its treatment window still has more room for improvement. ADC drugs are designed to improve chemotherapeutic drugs. Traditional chemotherapeutic drugs do not have the specificity of identifying tumors. Antibodies target cytotoxic drugs to cancer cells to increase the proportion of drug molecules reaching the tumor, thereby reducing the minimum effective dose of chemotherapeutics and increasing resistance. Receive the dose, broaden the treatment window. However, due to linkers and connection methods, the first and second-generation ADC drugs still have off-target toxicity and produce uneven antibody conjugates, making the therapeutic window still narrow. Now scientists have developed a variety of technologies to Optimize ADC drugs, such as antibody optimization to improve affinity, site-specific coupling technology to improve product uniformity, and new effector molecules to enhance molecular toxicity. The therapeutic window of ADC drugs has been greatly widened, the therapeutic index has risen, and the effect of ADC drugs has increased. And there are also obvious breakthroughs in the side killer effect and low expression targets.
The by-killer effect comes from the ADC of the degradable linker, which releases toxins after the linker is degraded. When the toxin has good membrane permeability, it can penetrate the cell membrane to attack nearby cancer cells. Due to the clustering effect of tumor cells, the appearance of the side-killing effect makes ADC more powerful in blasting. Therefore, the use of degradable linkers needs to take into account the balance of both, which not only requires higher stability of ADC in vivo circulation but also requires a better killing effect. In recent years, more and more evidence in solid tumors has shown that the side-killer effect of ADC drugs is very important, especially the toxins in ADC drugs such as Enhertu and Trodvlvy, which have been successful in recent years, have relatively obvious side-killer effects.
Due to factors such as strong targeting and toxin aggressiveness, some ADC drugs also show effective effects in cancers with low target expression levels. This application breaks through the limitations of targeted drug applications and is expected to become one of the development directions of ADC drugs in the future. At present, many star drugs around the world are exploring the application of ADC in tumors with low or no target expression.
Table 1: ADC drugs for tumors with low or no target expression (partial list).
|DS-8201 (Trastuzumab deruxtecan)||ERBB2||Phase I||A topoisomerase I inhibitor payload, a derivative of the camptothecin analog exatecan (DXd; DX-8951 derivative).||A tetrapeptide linker, Gly-Phe-Leu-Gly (GFLG). An average of 8 cysteinyl||Solid tumors (including Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer)||Daiichi Sankyo Inc.|
|IMMU-132 (Sacituzumab govitecan)||TACSTD2 (tumor-associated calcium signal transducer 2)||Phase II, Phase III||Camptothecin analog (SN38)||Carbonate||Metastatic Solid tumor, epithelial cancers | bladder, colorectal, head and neck, kidney, NSCLC, SCLC, ovary, pancreas, prostate, gastrointestina||Immunomedics|
|RC48 (Disitamab Vedotin)||EGFR2||Phase I (Sold Tumors) Phase II (Advanced Breast Cancers)||Monomethyl Auristatin E (MMAE)||A cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker. On an average of 4 cysteinyl||Solid Tumors, Advanced Breast Cancer||Yantai Rongchang Biological Engineering; RemeGen (Shandong China), and MabPlex|
Because end-line/refractory cancers are more tolerant of toxic side effects, although ADC drugs have some side effects, the benefits to such patients are expected to outweigh the risks. Therefore, after sufficient clinical evaluation, future ADC drugs It is also expected to have a better performance in the treatment of end-line/relapsed and refractory tumors.
In addition to finding more toxic toxins, optimizing connection technology, and optimizing antibodies, ADC drugs are also exploring other ways to improve, such as the development of miniaturized antibody conjugate drugs (single-chain antibody scFv, Fab, diabody), and new carriers (TRAIL). And its receptors), etc., looking forward to further exploring the application potential of ADC drugs.