From silence to rise, the drug "missiles" that target cancer cells have finally broken into butterflies.

The human struggle with cancer has a long history, but to this day, cancer is still a disease that we fear.
cancer is genetically variable, and the drugs and methods we use to treat it are very limited.
addition to the "eternal life" of cancer cells, the scary thing about cancer lies in its ability to metastasite.
, metastasis is often a fatal blow to patients with advanced cancer.
how to accurately identify cancer cells becomes a prerequisite for treatment when cancer cells spread throughout the body as blood spreads throughout the body.
need to "find it" before you can "destroy it".
scientists have worked so hard for this.
, for a long time, cytotoxic drugs were the main "weapon" of the human fight against cancer, commonly referred to as "chemotherapy".
traditional chemotherapy drugs have a strong attack, cell killing advantage is obvious, but its side effects are also significant.
traditional chemotherapy drug is not selective, will be aimlessly wandering within the body.
well known that in order to achieve therapeutic results, the drug needs to reach a certain concentration in the effective area.
therefore, in order for the drug to reach an adequate therapeutic dose in the target area, the overall intake needs to be increased.
because of the "non-differentiated attack" attribute, traditional chemotherapy drugs attack cancer cells at the same time, the damage to normal cells can not be avoided, and finally, often lead to "injury to the enemy a thousand self-injury."
, scientists began to think about how they could guide the drug "where to go."
we want drugs to destroy cancer cells in the body as precisely as missiles, but in fact, it's not easy, " he said.
targeting strategies, there are many differences between precisely guiding cancer cells and normal cells, and scientists are trying to develop drug-targeted strategies based on these differences.
surface antigen is one of them.
of the unique antigens on the surface of the cancer cells are overexpressed, significantly different from the normal cell surface.
monoclonal antibodies can be combined with such antigens with a high degree of selectivity to achieve precise positioning of cancer cells.
although antibodies have significant selective advantages, their cell-killing effects are often limited.
, the scientists proposed a "strong and strong union" targeting strategy.
a targeted treatment method called antibody concatenation drug, it has become one of the hot directions in the development of anti-cancer drugs.
This is an anti-cancer "combination punch" that binds large molecules to small molecules, complementing the precise identification of antibodies with the "killing" effects of payload drugs, which combine to create a drug "missile" that destroys cancer cells by combining linker. The structure of
antibody concatenation drugs can be divided into three parts: cytotoxic drugs, as payloads, to kill, antibodies have a high degree of cellular selectivity, as a guiding part, to guide the precise attack in the body, antibody parts and load drugs through the linker binding, forming a strong combination of drug "missiles."
(Picture Source: Resources) Has a much longer half-life of monoclonal antibodies than conventional cytotoxic drugs and can last for weeks. the
combination of "missiles" also "genetically" antibodies for several weeks of half-life, not only to help the load of cytotoxic drugs accurately attack cancer cells, but also to obtain longer treatment time in the body, greatly reducing the side effects of the simple use of cytotoxic drugs.
, the advantages and disadvantages of installing advanced "guidance" system drug "missiles" how to kill the target cells? The classical effect mechanism of antibody concatenation drugs (Image source: Resources: 1) Usually the antibody portion of antibody concatenation drugs binds to antigens on the surface of cancer cells, which swallow antigen-antibody complexes into the cells, and then, under the role of lysolyse degradation, release cytotoxic load drugs, target DNA or microtectrin, and mediat the apoptosis of target cells.
if the load drug can spread through the cell membrane, killing the surrounding cells, it will produce what is commonly referred to as the "bystander effect", the surrounding cells will also be within range of action.
addition, antibody concathing drugs can be released directly near the cell, rather than through cell internalization.
this approach targets a wider range of antigens and does not have to rely too much on the high expression of antigens on the cell surface, while avoiding inefficient transport within cells.
Of course, this effect also reduces selectivity, with some load drugs acting in non-target areas, injuring "innocent" normal cells and tissues, commonly referred to as "off-target toxicity."
A classic mechanism of action, through in-cell swallowing and in-cell load drug release effect; B non-internalized extracellular mechanism; (Image source: Reference 2) developing bottlenecks that challenge many, in fact, the concept of antibody contouring drugs dates back to the 1980s.
2000, the FDA approved mylotarg, the first antibody concathing drug, which fell silent after it was de-listed in 2010 because of toxicity.
is because the concept may seem simple, but scientists have found that it is challenging in practice.
want to selectively "transport" cytotoxic drugs directly into tumor cells, while playing an anti-cancer role while avoiding the effects on healthy cells, the role of the connecting son is crucial.
because of the low oral biousing of antibody concatenation drugs, they are often given intravenously.
if the connectant releases the drug too early, it can produce off-target toxicity in the blood, and if the target cell region is unable to release the load drug effectively, it can also affect the lethal effect on cancer cells.
therefore, an excellent connector to do, for the load drug "should not be released when never let go, when the release of the machine."
Overall, good concatenations usually require three main characteristics: first, a high degree of stability in the blood circulation;
the synthesis of concatenation and load drugs is one of the keys to the development process of new drugs, but there are many problems that antibody concatenation drugs need to solve.
Due to process problems, traditional methods can not control which site the load drug will connect to the antibody, will form a mixture of antibodies and different numbers of load drug connection, in addition, as a connection site of natural amino acids easy to break in the body, the overall stability of the drug is also a huge challenge.
, the industry has invested a lot of research and development efforts and resources in recent years to optimize the structure of antibody concatenation drugs.
with the breakthrough of key technologies, antibody contipation drugs finally broke into butterflies, and was approved in succession.
, there are many successful precedents for the connections used in antibody concathing drugs.
, peptide structure is a very widely used one, and is also a very common and important structural unit in many antibody concatenate drugs in the clinical stage.
in 2019, the FDA approved three antibody concalyptum drugs, all containing polypeptide structure of the linker, two of which are load drugs (payload) is also a peptide structure.
(see Figures 6, 7, 8 below) The FDA approved peptides and oligonucleotides in 2019, three of which are antibody concatenation drugs containing peptide structures (Image source: References: 3) Polypeptides can be considered as a "fragmentary" structure of proteins that can be disassembled into a specific amino acid molecule.
, the scientific community classes between 2 and 100 amino acids connected by the alamide bond as peptides.
is well known that amino acid sequences are specific, so proteases can be highly selectively cut at specific sequence locations.
Although peptides are not complex in protein structure, the designed peptide sequence can also be selectively cut by specific enzymes, and the purposeful introduction of non-natural amino acids can make the connections of many peptide structures more stable during in vivo transport.
this significant advantage, making it possible to release load drugs with precision and payload.
as early as 2009, Pharmaceutical Mingkangde Chemical Services set up a polypeptide chemistry research team to provide customers with various research services for peptide chemical synthesis.
recent years, the polypeptide chemistry research team has accumulated extensive experience in the synthesis of a key part of antibody concalyptum drugs: concathing sub-load drugs.
antibody coupling drugs and their analog-related businesses are already one of the core businesses of the Peptides team in Chemical Services, and by working with the pharmaceutical industry, industry-leading integrated and end-to-end capabilities of small molecules (including connectors and load drugs), peptides and oligonucleotides have been built to provide customers with a one-stop service from research and development to commercial production, enabling customers to better, faster and more cost-effectively bring to market the antibody couplings needed by patients.
based on the deep accumulation of capacity, Pharmaceutical Mingkangde Chemical Services can provide partners with high-quality peptide molecular synthesis solutions, the chemical synthesis of oligonucleotides, peptides and small molecular integration platform polypeptide connectors is unique in itself.
addition, peptide analogants that can play the same role as "guidance" and peptide cytotoxic drugs have become important directions for targeted drug exploration.
Conventional peptide synthesis is carried out through solid phase carriers, but for different amino acids, especially many non-natural modified amino acids, how to screen out efficient shrink reagents, de-protection conditions and purification conditions are very critical.
Through the combination of solid phase and liquid, The drug Mingkangde not only has excellent performance in the synthesis of non-natural amino acid polypeptide products, but also has a wealth of accumulation in the customization of special amino acids, which can support partners in the development and exploration of targeted drugs, including antibody concatenation drugs.
the development of targeted drugs is one of human dreams in the fight against cancer, and we deeply hope that the drug will destroy cancer cells while greatly reducing the suffering of patients.
recent years, antibody contipation drugs are highly anticipated, become the hot development direction of disease treatment, the number of drugs in research continues to climb.
following the approval of three antibody concatenation drugs in 2019, in the first half of this year, the FDA approved the launch of the antibody contupulsive drug Trodelvy (sacituzumab govitecan-hziy) to treat patients with triple negative breast cancer.
is also the fourth antibody concathing drug approved by the FDA in nearly a year and a half, accounting for 50 percent of the total antibody concathing drugs approved by the FDA.
industry's key technologies have produced the flowering results of antibody conjoined drugs and are thriving.
For antibody concatenation drugs, there will be a lot of pioneering work in the future, requiring technical support and breakthroughs, such as exploring more excellent connectors, the location of antibody concatenation, antibody similarity synthesis and so on.
hope that the ability of the Pharmaceutical Mingkangde platform in the development of peptide drugs will continue to empower the vast number of partners in pharmaceutical innovation.
expect more and better antibody concathing drugs to be available as soon as possible for the benefit of patients.
: s1. Nagavendra Kommineni, Palpandi Pandi et al., (2019). Antibody drug conjugates: Development, characterization, and regulatory thinks. Polym Adv Technol, 2019;1-17, DOI: 10.1002/pat.4789. Cleavable linkers in antibody-drugjugates. Chem. Soc. Rev., 2019, 48, 4361-4374, DOI: 10.1039/c8cs00676h. 2019 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals 2020, 13, 40, DOI:10.3390/ph13030040▽ attention to the public number of WeChat.