A Quick Look at ADC—A New Favorite of Cancer Treatment

Traditional chemotherapeutics work by killing actively growing cells, but cannot accurately identify tumor cells. Therefore, when the tumor cells are killed, normal cells are also destroyed, resulting in larger adverse reactions. With the development of modern medicine, traditional extensive treatment gradually converted into precise and individualized treatment, which is not only reflected in the treatment methods but also the higher requirements for anti-tumor drugs. For molecularly targeted therapy, only tumor-specific molecules and genes are targets to interfere with tumor cells or their induced microenvironment, and induce tumor cell death or loss of function. The design idea of ADC is to couple an antibody with the cytotoxic drug to simultaneously exert the high specificity of antibodies and the high toxicity of cytotoxin, and use the highly targeted binding of antibody-antigen to deliver the drug to the tumor sites, concentrating the powerful cell killing ability of cytotoxic drugs on tumor cells, and reduce the toxic side effects on normal tissues. An ADC is composed of a monoclonal antibody (mAb), linker, and a payload. An ADC relies on the specificity and targeting of the monoclonal antibody to tumor cell-related antigens to reach tumor cells and enter the cell through endocytosis. The linker (https://www.creative-biolabs.com/adc/classify-druglnk-products-2.htm) breaks under the action of low pH in the cell or lysosomal protein, releasing cytotoxic drugs. The advent of ADC drugs fills the gap between antibody drugs and traditional chemotherapy drugs and improves the specificity of drugs. Advantages:rnPrecise targeting rather than indiscriminate attacks, reduce normal tissue damage.rnThe internalization of cytotoxic drugs is more efficient.rnTherapeutic potential of pan-cancer species.rnBystander effect: also function on patients with low expression of tumor antigens. 1. ADC targeting HER-2 HER2 is a common oncogene that is overexpressed in many cancers, such as gastric cancer and breast cancer. 15%-25% of new breast cancer patients have HER2 gene amplification or protein overexpression. Hercelium T-DM1 (Enmetrastuzumab Kadcyla)rnConjugation: mAb targeting HER2 + DM1 cytotoxic agent DS-8201 (trastuzumab deruxtecan, Enhertu)rnConjugation: mAb targeting HER2 + Dxd (DNA topoisomerase I inhibitor) 2. ADC targeting HER3 In EGFR-mutated non-small cell lung cancer (NSCLC), the frequency of HER3 overexpression is as high as 75%. After EGFR-targeted drug resistance, the expression of HER3 protein on the surface of most non-small cell tumors increases. It is related to cancer metastasis and survival time of NSCLC patients. U3-1402 (Patritumab Deruxtecan)rnConjugation: mAb targeting HER3 + Dxd (DNA topoisomerase I inhibitor) 3. ADC targeting Trop-2 Trop2 is a tumor-associated antigen expressed in a variety of cancer types, especially non-small cell lung cancer and breast cancer. Among them, expert Rebecca S. Heist believes that a high expression is found in 64% of non-small cell adenocarcinomas and 75% of non-small cell squamous cell carcinomas. More than 90% of triple-negative breast cancer TNBC has abnormal expression of Trop-2, which is related to poor prognosis. DS-1062 (Datopotamab Deruxtecan)rnConjugation: mAb targeting Trop-2 + Dxd (DNA topoisomerase I inhibitor) Trodelvy (sacituzumab govitecan or IMMU-132)rnConjugation: mAb targeting Trop-2 + cytotoxin SN38 BAT8003, SKB264, DAC-002, etc. 4. ADC targeting TF receptors Many tumor cells overexpress tissue factor receptors on the surface, and its abnormal expression is related to the poor prognosis of patients and increased metastasis. Tisotumab Vedotin (TV)rnConjugation: mAb targeting TF receptor + microtubule blocker MMAE 5. ADC targeting Nectin-4 receptor Nectin-4 is an adhesion protein highly expressed on urothelial carcinoma UC, breast cancer, gastric cancer, lung adenocarcinoma, and other solid tumors. Padcev (EV Enfortumab Vedotin)rnConjugation: human IgG1 mAb targeting Nectin-4 + microtubule blocker MMAE 6. Other ADC drugs Adcetris, Brentuximab vedotin, CD30 conjugated antibodyrnBesponsa, Inotuzumab ozogamicin, CD22 conjugated antibodyrnMylotarg, Gemtuzumab ozogamicin, CD33 conjugated antibodyrnPolivy, polatuzumab vedotin-piiq, CD79 conjugated antibody The ideal ADC should be stable in the blood with short half-life, fast metabolism, but not accumulating toxicity. High target specificity, strong drug penetration and killing, desired DAR, and balanced distribution are preferred properties.