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

In addition to the "immorality" of cancer cells, the terrible thing about cancer is its ability to metaseter.
for patients with advanced cancer, metastasis is often a fatal blow.
how to accurately identify cancer cells as blood spreads through multiple tissue organs throughout the body has become a prerequisite for treatment.
you have to "find it" before you can "destroy it."
scientists have worked so hard for this.
, cytotoxic drugs have been the main "weapon" in the fight against cancer in humans for a long time, commonly known as chemotherapy.
traditional chemotherapy drugs have a strong attack, cell killing advantage is obvious, but its side effects are also significant.
traditional chemotherapy drugs are poorly selected and can wander aimlessly around the body.
well known that in order to achieve therapeutic results, the drug needs to reach a certain concentration in the starting area.
, in order for the drug to reach an adequate therapeutic dose in the target area, it is necessary to increase the overall intake.
because of the "non-differentiated attack" attribute, traditional chemotherapy drugs in the attack on cancer cells at the same time, the damage to normal cells can not be avoided, and finally, often lead to "injury of the enemy 1,000 self-damage 800."
, scientists began to think about how they could guide the drug "to where and where."
hope that the drug can destroy cancer cells in the body like a missile, but in fact, it's not easy.
are many differences between precision-guided cancer cells and normal cells, and scientists are trying to develop drug-targeted strategies based on these differences.
surface antigens are one of them.
unique antigens overexpressed on the surface of cancer cells, significantly different from normal cell surfaces.
monoclonal antibodies can be combined with such antigens with a high degree of selectivity to achieve precise positioning of cancer cells.
antibody has obvious selective advantages, its cell-killing effect is often limited.
, the scientists proposed a "strong union" targeting strategy.
a targeted treatment called antibody association drugs, and began to become one of the hot topics of cancer drug research and development.
This is an anti-cancer "combination punch" in which large molecules bind to small molecules, complementing the precise recognition of antibodies with the "killing" effects of payloads, and combining them with linker to create a drug "missile" that destroys cancer cells. The structure of
antibody association drugs can be divided into three parts: cytotoxic drugs, acting as payloads, acting as killer effects;
(Photo Source: Reference 1) Monoclonal antibodies have a much longer half-life than conventional cytotoxic drugs and can last up to several weeks.
combination of "missiles" also "inherited" antibodies up to several weeks of half-life, not only to help load cytotoxic drugs accurately attack cancer cells, but also in the body to obtain longer treatment time, greatly reducing the side effects of simply using cytotoxic drugs.
the internal cells, the advantages and disadvantages, then, the installation of advanced "guidance" system of the drug "missile" is how to kill the target cells?The classic actuation mechanism of antibody-coupled drugs (Photo Source: Resources) Usually the antibody portion of the antibody-coupled drug binds to antigens on the surface of cancer cells, which swallow antigen-antibody complexes into the cells and then, under the effect of lysosome degradation, release cytotoxic load drugs, target dna or micro-tube proteins, and mediate apoptosis of target cells.
if the load drug can spread through the cell membrane, killing the surrounding cells, there will be what is commonly referred to as the "bystander effect" and the surrounding cells will be within range.
addition, antibody-coupled drugs can also be present not through cell internalization, but directly near the cell release of drugs.
this approach targets a wider range of antigens without over-reliance on the high expression of cell surface antigens, while avoiding inefficient transport within cells.
Of course, this form of effectiveness also reduces selectivity, with some load drugs acting in non-target areas, hurting "innocent" normal cells and tissues, commonly referred to as "off-target toxicity."
A classic mechanism of action, through in-cell swallowing and release of in-cell load drugs, B non-internalized extracellular action mechanism, (Photo source: References.
2000, the FDA approved the first antibody-coupled drug, Mylotarg, to market, and the antibody-coupled drug fell silent in 2010 because of toxicity.
that's because the concept may seem simple, but scientists have found it challenging in practice.
want to selectively "transport" cytotoxic drugs directly to tumor cells, while playing an anti-cancer role while avoiding the effects on healthy cells, the role of connecting children is critical.
, antibody-coupled drugs are often administered intravenously because of their low oral bio-utilization.
if the connecting son releases the drug too early, it can produce off-target toxicity in the blood, and if the target cell area is not able to effectively release the load drug, it will affect the lethal effect on cancer cells.
therefore, an excellent connection to do, for the load drug "should not be released when never let go, when the release when the machine broke."
In general, excellent connecting devices often require three main characteristics: first, a high degree of stability in the blood circulation;
the synthesis of anti-coupled connections and load drugs is one of the keys to the development of new drugs, but there are many problems that antibody-coupled drugs need to solve.
Due to process problems, traditional methods can not control which point the load drug will be connected to the antibody, will form a mixture of antibodies connected to different numbers of load drugs, in addition, as a connection point of natural amino acids easily 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 optimizing the structure of antibody-coupled drugs in recent years.
with the breakthrough of key technologies, antibody-coupled drugs finally broke into butterflies, and were approved in succession.
currently, there are many successful precedents for the connections used in antibody-coupled drugs.
, peptide-like structures are a very widely used type and are important structural units that are very common in many antibody association drugs in the current clinical phase.
in 2019, the FDA approved three antibody-coupled drugs, all containing peptide-structured linkers, two of which are also peptide-like.
(see Figures 6, 7, 8 below) The FDA's approval of peptides and oligonucleotides in 2019 has yielded considerable results, three of which are antibody-coupled drugs containing peptide structures (Photo Source: References.
, the scientific community classifies molecules made up of 2 to 100 amino acids connected by amide bonds as peptides.
is well known that amino acid sequences are specific, so proteases can be highly selective in specific sequence locations.
although there is no protein structure complex, but the design of peptide sequence can also be selected by specific enzymes cutting, and the purposeful introduction of non-natural amino acids, can make the multi-peptide structure of the connector can be more stable during in vivo transport.
this significant advantage, making it possible to release load drugs precisely and effectively.
as early as 2009, Pharmaceutical Mingkangde Chemical Services set up a polypeptide chemical research team to provide customers with a variety of research services for peptide chemical synthesis.
, the peptide chemistry team has gained extensive experience in the synthesis of antibody-coupled drugs, a key part of the antibody-load drug.
Antibody Coupling Drugs and their analogues-related business is already one of the core businesses of the Peptides team of chemical services, and by working with the pharmaceutical industry, we have built the industry-leading integration and end-to-end capabilities of small molecules (including connecting sub- and load drugs), peptides and oligonucleotides, providing 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 antibodys they need.
based on deep capacity accumulation, Pharmaceutical Mingkangde Chemical Services is able to provide partners with high-quality peptide molecular synthesis solutions, the chemical synthesis of oligonucleotides, peptides and small molecule integration platform peptide connectors at Changzhou base of the pharmaceutical industry is unique in itself.
addition, peptide analogoons that can also target "guidance" and peptide cytotoxic drugs have become important directions for targeted drug exploration.
The conventional polypeptide synthesis is carried out through solid-phase vectors, 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, Pharmaceutical Mingkang has not only excellent performance in the synthesis of non-natural amino acid peptide 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 conceding drugs.
that the development of targeted drugs is one of the human dreams in the fight against cancer, and we deeply hope that the drug will destroy cancer cells while minimizing the suffering of patients.
years, antibody association drugs have been highly anticipated, become a hot development direction of disease treatment, the number of drugs in research continues to climb.
in the first half of this year, the FDA approved the launch of the antibody coupled drug Trodelvy (sacituzumab govitecan-hziy) to treat patients with triple negative breast cancer, following the approval of three antibody-coupled drugs in 2019.
is also the fourth antibody-coupled drug approved by the FDA in nearly a year and a half, accounting for 50 percent of the FDA-approved antibody-coupled drugs.
breakthroughs in key technologies in the pharmaceutical industry have led to the flowering of antibody-coupled drugs.
There is a lot of ground-breaking work ahead for antibody-coupled drugs that will require technical support and breakthroughs, such as exploring more excellent connecting devices, positioning mates with antibodies, and synthesis of antibody similars.
hope that the drug Mingkang platform in the development of peptide drug capabilities, continue to empower the vast number of partners in pharmaceutical innovation.
expect more and better antibody-coupled drugs to be available as soon as possible for the benefit of the vast number of patients.
references: ( 1 ) Nagavendra Kommineni, Palpandi Pandi et al., (2019). Antibody drug conjugates: Development, characterization, and regulatorys. Polym Adv Technol, 2019; 1-17, DOI: 10.1002/pat.4789 (2) Jonathan D. Bargh, a Albert Isidro-Llobet et al., (2019). Cleavable linkers in antibody-drug conjugates. Chem. Soc. Rev., 2019, 48, 4361-4374, DOI: 10.1039/c8cs00676h , Danah Al Shaer, Othman Al Musaimi et al., (2020). 2019 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals 2020, 13, 40, DOI:10.3390/ph13030040.