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Progress in the Development of Targeted Anti-Tumor Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) are conjugated products of monoclonal antibodies (mAbs) and cytotoxic small molecules. In tumor treatment, although monoclonal antibodies have good targeting properties, most of them target extracellular or cell surface antigens, have weak anti-tumor activity, have limited therapeutic effect on solid tumors, and are more likely to develop drug resistance; conventional anti-tumor chemotherapy Although drugs have high anti-tumor cell activity, they lack targeting and often accidentally damage normal cells in the body, causing serious side effects. Antibody-drug conjugates complement each other perfectly, combining the high specificity of antibodies with the high toxicity of cytotoxic drugs to tumors. They can specifically kill tumor cells without damaging normal tissue cells, and are clinically highly effective and low-cost.

Figure 1. The history of ADC development.

Mechanism of Action of ADC

As a new targeted drug delivery system using monoclonal antibodies as carriers, ADC consists of three parts: monoclonal antibodies, cytotoxic small molecule drugs, and antibody-drug linkers. The main function of monoclonal antibodies is as a drug carrier, controlling the targeting of ADC drugs, and targeting and enriching the “warhead” – cytotoxic small molecule drugs to the tumor site. The target antigen it binds to must be expressed with high specificity in tumor cells or tumor microenvironment. Cytotoxic small molecule drugs are the second key factor in ADC drug design. The anti-tumor effect of ADC drugs mainly depends on the killing effect of the selected cytotoxic small molecule drugs. The linker mainly acts as a bridge to stably couple the monoclonal antibody to the cytotoxic small molecule. It carries the functions of ADC stability, water solubility, and intra-tumor cell release. ADC enters the blood circulation by intravenous injection. After entering the tumor tissue, it binds to the antigen on the surface of the tumor cells. Then, under the mediation of the receptor, it is mostly endocytosis through clathrin traction and enters the tumor cell lysosome, where it is released. Cytotoxic small molecules combine with the DNA, RNA, tubulin, etc. of tumor cells, affecting their replication or mitosis, and produce anti-tumor effects. In addition to the cytotoxic effects of cytotoxic small molecules (payload), the inhibition of tumor cell receptor signaling pathways mediated by monoclonal antibodies, and the immune response mediated by the antibody Fc domain and payload can all assist the efficacy of ADCs. The selection of antibodies, target antigens, cytotoxins, linkers and conjugation methods are all critical to the success of ADC drug development.

Monoclonal Antibody Selection

The ADC antibody part not only serves as a cytotoxic carrier, but also assumes a targeting role, and can induce endocytosis mediated by target antigens on the surface of tumor cells. Monoclonal antibodies are generally specific monoclonal antibodies designed against target antigens on the surface of tumor cells. They are produced from a single B cell clone and have the characteristics of high purity, high sensitivity, strong specificity, less cross-reaction, and low preparation cost. Usually Prepared using hybridoma technology. In addition to having low immunogenicity, an ideal monoclonal antibody should also have the following characteristics: high specificity, that is, good targeting, the ability to specifically bind to target cells and high affinity, and after endocytosis by target cells, It results in the effective release of the carried small cytotoxic molecules; no negative feedback occurs after binding to the antigen; and its own characteristics do not change after being coupled with toxic drugs. At present, monoclonal antibodies generally choose IgG with longer half-life, mostly IgG1, IgG2 and IgG4.

ADC Linker

The linker that connects the antibody and the toxin must remain stable in the blood circulation for a long time to prevent the early release of toxic small molecules into the blood and cause serious adverse reactions and reduce the efficacy. After entering the cancer cells, it is necessary to ensure the effectiveness of the “warhead” cytotoxic molecules freed. ADC generally uses covalent bonds such as peptide bonds, disulfide bonds, and thioether bonds to connect monoclonal antibodies and toxic small molecules. Linkers are divided into two categories: non-cleavable and cleavable. Non-cleavable linkers have good stability, such as thioether linkers. Kadcyla, which treats breast cancer, uses a stable thioether linker to link the maytansine derivative DM1 to the antibody. According to different cleavage mechanisms, cleavable linkers are divided into chemically cleavable linkers and enzymatic cleavable linkers. The former includes hydrazone linkers, etc., and the latter includes peptide linkers, etc. Adcetris, developed and marketed by Seattle Genetics for the treatment of Hodgkin lymphoma, successfully conjugates MMAE, a synthetic derivative of the microtubule inhibitor Aplysia toxin 10, to the monoclonal antibody cAC10 using a valine-citrulline dipeptide linker. The connection methods of linkers are divided into non-fixed-point coupling method and fixed-point coupling method. Since there are a large number of functional groups on the antibody molecule, the coupling reaction can be performed at multiple sites using a non-directed coupling method. The final product of the coupled ADC is a mixture with different drug-to-antibody ratios (DAR), resulting in a complex product. The pharmacology, pharmacokinetics and pharmacodynamics are not easy to control, and the product stability is poor. The connected cytotoxic molecules are easy to fall off and cause toxic side effects. Problems are prone to occur in its analysis, identification and product quality control. These problems can be solved by using fixed-site coupling technology. This technology mostly involves modifying and transforming antibodies to connect cytotoxic molecules to specific sites on the antibody. This technology greatly improves the uniformity and purity of the ADC and can effectively control the drug-antibody ratio. As well as key quality attributes such as drug loading distribution, it facilitates analysis, identification and quality control, reduces drug side effects, and increases the drug treatment window. For Enhertu, which will be launched in 2019, and Trodelvy, which will be launched in 2020, the connection strategy of the linker is fixed-site coupling. Fixed-site coupling has become a trend in the research and development and innovation of the new generation of ADCs.

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