Outline Of ADC Drug Manufacturing Preparation Process
According to the latest global cancer burden data for 2020 released by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO), China has become a true "cancer country".
In 2020, there will be 19.29 million new cancer cases in the world, of which 4.57 million will be new cancer patients in China, with 2.48 million males and 2.09 million females, accounting for 23.7% of the global cancer burden, and the number of new cancer cases far exceeds the number of new cancer cases in the rest of the world. 9.96 million global cancer deaths were reported in 2020, of which 3.00 million deaths were in China, with 1.82 million males and 1.18 million females, accounting for 30% of the global cancer deaths.
Globally, the cancer burden is projected to increase by 50% in 2040 compared to 2020, meanwhile the number of brand-new cancer cases will reach nearly 30 million, due to an increasing population aging.
Given such a large number of morbidity and mortality, the development of effective antitumor drugs that can improve the current stage of tumor treatment as well as prolong patient survival is urgently needed and has now become one of the primary goals of worldwide new drug developers. Over the past decades, targeted therapies have received increasing attention from researchers for their controlled healing efficacy and safety. Antibodies being naturally present in the body's immune system, and antibody drugs have naturally become one of the research hotspots. Judging from the global drug sales list in recent years, antibody-coupled drugs have been developing extremely rapidly, showing good market prospects.
Antibody-coupled drug (ADC) is a new type of highly effective biopharmaceutical that connects antibodies with biologically active small molecule cytotoxic loads through linkers, which is one of the faster-developing drug classes in oncology in recent years, and it has now become a hot direction in the research and development of antitumor drugs, opening up a new chapter in the treatment of tumors.
Among them, antibodies can recognize tumor antigens with high specificity, and after intravenous administration, the drugs are distributed to tumor tissues through blood circulation and bind to tumor surface antigens.The complexes of ADCs and antigens undergo endocytosis, internalizing the small molecule cytotoxic load they carry into tumor cells, being transported to lysosomes to be released in a highly efficient and active form, which induces apoptosis of cancer cells through DNA damage or inhibition of microtubule synthesis. Due to the dual advantages of high targeting of monoclonal antibody drugs and high activity of cytotoxicity in tumor tissues, ADC drugs can efficiently kill and injure tumor cells, with lower adverse effects than chemotherapeutic drugs, and better efficacy than traditional antibody tumor drugs, which is the hotspot of tumor innovative drug research and development in recent years.
Manufacturing process of ADC drugs
ADC production and preparation process is complex, according to the different coupling method and process, the overall process can be roughly divided into three steps: monoclonal antibody production, cytotoxic drug/linker production, and ADC stock solution and preparation production.
Monoclonal antibody production: Antibody molecules are the core components of ADC drugs, and their activity is critical to the efficacy of the drug. In the production process, the antibody molecule first needs to be activated. Chemical methods, such as the use of activators (e.g., sulfonates) or recombinant antibody engineering techniques, are usually employed to couple specific functional groups of the antibody molecule with linkers or toxins. The activated antibody molecule has higher reactivity and can bind specifically to the target antigen.
Cytotoxic Drugs/Linker Production: The coupling of linker-toxin to antibody is one of the key steps in the preparation of ADC drugs. A linker is a chemical that connects an antibody to a toxin molecule, usually a compound with high affinity, high stability and low toxicity. The toxin molecule is used to kill the target cell or inhibit its growth. Through the bridging role of the linker, the antibody and toxin molecules are coupled to form the active ingredient of the ADC drug. The coupling reaction strategy and process, which determines key quality attributes such as the amount of drug loading and the mode of drug loading distribution, are directly related to the effectiveness and safety of ADC drugs. An ideal ADC coupling strategy or technology needs to have the following characteristics: A. The chemical bonds or groups in the binding portion of the antibody and the small molecule should be sufficiently stable to ensure their stability in the circulatory system; B. The coupling site will not interfere with the function of the antibody, in particular, the specificity and high affinity of the binding to the target antigen; C. The reaction involved in the coupling process must be sufficiently selective and reactive, and at the same time, it should be easy to control the drug loading and drug loading distribution.
Current ADC coupling technologies can be generally classified into two categories. One is the coupling technology (non-site-specific coupling) mediated by the use of naturally reactive amino acid residues in the antibody sequence (e.g., the side-chain amino group of surface lysine and the sparing group of the inter-chain disulfide bond reduction), which is adopted by 13 kinds of the ADC drugs that are currently on the market; Another type of coupling technology is to introduce a reactive group into the specific site of the antibody by means of chemical modification, genetic engineering technology or enzyme modification, and then coupled with a toxin small molecule to realize site-specific coupling technology (targeted coupling). Such techniques include engineered cysteine site insertion, non-natural amino acid site insertion, enzyme-mediated and N-glycosylation-mediated coupling and so on.
ADC stock and preparation production: The final step in the preparation of ADC drugs is to carry out ADC stock and preparation production. The purification step removes uncoupled antibody, linker and toxin molecules, as well as impurities and by-products generated during the reaction process. The purification process usually employs various chromatographic techniques (e.g., gel chromatography, ion exchange chromatography, etc.) and filtration techniques (e.g., ultrafiltration, nanofiltration, etc.). After purification, the required ADC drug is characterized by high purity and low impurities, and can meet the needs of clinical treatment.
As can be seen from the flow chart of ADC drug production and preparation, whether it is the preparation of monoclonal antibody, the coupling of loads, or the production of ADC stock solutions and preparation, they all need to be completed by membrane filtration technology (clarification of fermentation broths, buffer replacement, ultrafiltration penetration, and aseptic filtration, etc.).
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