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    Home > Biochemistry News > Biotechnology News > Anti-cancer missiles - ADC development challenges and responses.

    Anti-cancer missiles - ADC development challenges and responses.

    • Last Update: 2020-07-29
    • Source: Internet
    • Author: User
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    Chemotherapy is one of the main means of cancer treatment, but traditional chemotherapy drugs do not have tumor recognition specificity, easy to mistakenly injure normal cells, causing serious adverse reactions in patientsMolecular-targeted drugs are an important direction of current drug designAmong them, monoclonal antibody drugs have the advantages of strong targeting, high specificity and low incidence of serious adverse reactions, but their molecular weight is large, the effect of individual treatment is limitedAntibody Conjugate (Antibody-drug conjugate, ADC) connects monoclonal antibodies with small molecule chemotherapy drugs through a connecting sub, and installs a "positioning system" with monotoanti-drugs, which has both a high lysing potential for monoanti-resistance and the full lethality of chemotherapy drugsOn June 5, DrJenny Thirlway, head of the research and development team at Iksuda Therapeutics, a company dedicated to ADC development, published an article in Genetic Engineering and Biotechnology News exploring the challenges and solutions involved in payload effectiveness and conjugate stability in ADC developmentpicture source: Dr Jenny Thirlway of Genetic Engineering and Biotechnology News, says there is an urgent need for innovation in treatments to improve survival rates for cancer patients, in line with advances in testing and diagnosisAlthough significant progress has been made in many areas of indications, the mortality rate of some of the most difficult to treat in the physical tumors has not improved significantly since the 1970sStatistics show that the 10-year survival rate of esophageal and lung cancer has increased by less than 10%, while pancreatic cancer has not improved at allIn addition, even in cancers with improved survival rates such as melanoma, breast cancer and uterine cancer, fewer side effects and more effective treatment are still requiredADC is a new type of targeted treatment drug that promises to improve the treatment of traditional chemotherapyIt consists of three parts: tumor antigen-specific monoantiphoresis or antibody fragments, effective cytotoxic molecules (also known as loads), and connecting the first two partsADC antibodies bind to cancer cell surface target antigens, and then the ADC-target antigen complex is internalized through receptor-mediated internal swallowing, and finally the connection between the ADC antibody part and the load part is interrupted by the lysosome to release an effective cytotoxic load within the cell (below)The aDC's mechanism of action combines antibody targeting and potent cytotoxic agents to more effectively and selectively eradicate cancer cells while reducing toxic side effectsImage Source: Genetic Engineering and Biotechnology News' potential for ADC depends on optimizing each of the three "components" of the ADC puzzleThere are many factors that influence the clinical success of ADC, including antibody selection, heterogeneity and target antigen expression levels, payload efficacy and mechanism, binding strategies, and the choice of cutable and non-cut connectorsIn addition, in order to ensure a sufficiently wide treatment window, the bindings should be stabilized in the plasma to prevent the premature release of toxins in the whole body cycle, and once released in cells, the cytotoxic payload should be sufficient to eradicate the tumor Clinical status Currently, eight ADCs have been approved for listing: Brentuximab vedotin (Adcetris®), trastuzumab emtansine (Kadcyla ®), inotuzumab ozogamicin (Besponsa®), gemtuzumab ozoga Mylottin (Mylotarg®), polatuzumab vedotin (Polivy ™), enfortumab vedotin (Padcev ™), traszumab deruxtecan (Enhertu ®) and sacituzumab govitecan (Trodelvy ®) Among them, Adcetris®, Polivy ™ and Padcev ™ bind to the microtube protein inhibitor monoriositin E (monomethylalistatin E, MMAE) via Malayamide connectors, and Kadcyla ® bind seyoung-protein inhibitor mertanine (DM1) through Malayamide connectors Besponsa ® and Mylotarg ® bind to the DNA damage agent calicheamicin through a connective connection of acid-cracking, and Enhertu ® binds to the topological iasomelyase I inhibitor deruxtecan through Malayamide connectors The rapidly evolving pipeline reflects the clinical and commercial potential of ADC technology In 2019, nearly 90 ADCs will enter clinical trials Payload Development A toxin must be potefully sufficient to be effective The payload concentration in the target cells is usually low due to poor positioning and inadequate internalization of tumors In the ADC design, cytotoxic molecules ideally have ananamole-level efficacy in order to obtain the best efficacy Toxins should also have functional groups bound to the connector, or can be chemically modified to produce suitable sites for release in tumor cells In addition, the production cost of cytotoxins should be low The first generation of ADCs combines common chemotherapy drugs such as methotrexate, valproate and amycin, but even when combined with antibodies to increase specificity, they lack sufficient potency For example, although the cBR96-amycin bindingshowed hope in preclinical studies and progressed to The Phase II trial, its efficacy was insufficient, mainly due to the ineffectiveness of amycin payloads Because it is estimated that killing a cell requires between 4 000 and 12 million amycin molecules Generally, the level of expression of antigens per cell is below 1 million, which makes it difficult to reach critical concentrations of toxins Until recently, most ADCs under development used three types of toxins: calicheamycins (Wyeth/Pfizer), Maytansines (EIEGen) and Seattle Genetics This shows that finding the right payload in the ADC space is very difficult Auristatin and maytansine microtubal protein inhibitors have been widely used Auristatin blocks the assembly of microtubines, causing the G2/M cell cycle to abort Maytansine is a natural product isolated from Maytenus ovatus, an African shrub, and an effective microtube protein assembly inhibitor Although these bindings have been approved in some indications, they are not as effective in the indications of low target antigen expression or insensitive cells for microtubine suppression As a result, payload designs are pushed to address targets with insufficient microtube protein ADC activity, such as colon cancer DNA damage agent is another major type of toxin used in ADC development, which makes the aDC's effectiveness truly within the range of anamole, with some analogues exhibiting activity in the low-to-dermole range These include payloads for inotuzumab ozogamicin and gemtuzumab ozogamicin , an anti-tumor antibiotic , as well as other payloads including duocarmycins , topological isomer inhibitors , pyridoxandiazepines ( PBD ) and pyridine and diazepam ( IGN ) Increased efficacy also makes it possible to target tumor-specific antigens with low expression density Because the payload of DNA interaction is active in non-proliferative cells, the target can be extended to include tumor initiation cells (TICs) Toxicity and Stability Recently, clinical trial data show that ADCs containing PBD (naturally occurring anti-tumor antibiotics that bind to DNA grooves in a sequence-specific manner) cause serious toxicity problems in patients For example, the Phase III trial of vadastuximab talirine, which targets CD33, was aborted due to poor safety The failure of clinical trials led to a shift in the use of payloads from crosslinking agents to DNA alkylators For example, IGN has similar effects to PBD Cross-linked IGN also has adverse toxicity, but DNA alkylized IGN does not exhibit long-term or delayed toxicity In the first generation of ADCs, coupling stability is the second factor that affects effectiveness, which becomes more important as the payload spent is increased The first generation of ADCs bind sesame payloads mainly through the naturally occurring cysteine and lysine residues in the antibody structure However, the acid lysis connector in mylotarg ® is associated with nonspecific release of the drug in circulation The design of the second generation of ADCs is usually associated with malayamide-based coupling with pyridine-based proteins (such as albumin), but this has a tendency to be matesd through retro-Michael reactions As the field progresses, conjugate technology has greater stability For example, cyclic Malayamide stabilizes against de-coupling, and the ® technology of vinyl-based PermaLink does not have a retro-Michael reaction The third generation of ADCs utilize site-specific coupling strategies such as engineering cysteine and non-natural amino acids Compared to today's standard nursing chemotherapy, ADC offers more and more benefits in terms of efficacy and tolerability Emerging preclinical and clinical data will continue to guide The ADC's progress, and these results will also contribute to the continuous innovation of payload and conjugate strategies, potentially improving efficacy in solid tumors and broadening the range of treatable indications Related: Overcoming Challenges in The Development of Anticancer ADCs (Source: Genetic Engineering and Biotechnology News)
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