Aminoethyl-SS-ethylamine

Antibody-drug conjugates (ADCs) are a new type of macromolecular targeted drugs, and are currently mainly used to treat various tumors. ADC drugs are composed of three parts: antibodies that target surface receptors overexpressed by tumor cells, highly active cytotoxic small molecules, and linkers. Among them, the antibody part is responsible for accurately delivering ADC drug molecules to the surface of target cells, the linker is responsible for releasing toxin small molecules inside or on the surface of target cells, and the highly active cytotoxic small molecules efficiently kill tumor cells. Therefore, ADC is also commonly referred to as a "biological missile" or "magic bullet". The concept of magic bullet was proposed by Nobel Prize winner German scientist Paul Ehrlich in the early 20th century. It specifically refers to a type of molecule that can target and bind to target lesions and cure diseases. The time when this concept was materialized into a drug molecule in the form of antibody plus toxin small molecule was in 1957. Researchers coupled the chemotherapy drug methotrexate to the immunoglobulin of anti-L1210 leukemia cells through a diazo coupling reaction. The conjugate showed cell proliferation inhibition against the target cell L1210, while the conjugate coupled to conventional β-globulin had no effect. After more than ten years of development, in the mid-1970s, several ADCs prepared using animal-derived immunoglobulins showed definite efficacy in clinical trials. By the 1980s, the progress of monoclonal antibody development technology and recombinant protein production technology, the confirmation of multiple tumor markers, and the clarification of the target antigen-antibody mediated cellular endocytosis mechanism, at the same time, brought great impetus to the technical development of ADC drugs in multiple aspects such as targets, antibodies and linkers, which attracted drug research and development and biotechnology companies to increase investment in the development of ADC drugs in the 1990s, and the first ADC drug was approved for marketing in 2000.

Figure 1. Structures of GSH-cleavable triggers. (Su Z, et al.;2021)

The linker is responsible for linking ADC antibodies to cytotoxic small molecules and is critical to the safety and stability of ADC drugs. The ideal linker must be stable enough in the bloodstream to effectively prevent the ADC drug from releasing toxic small molecules into the bloodstream and normal tissues, and to maintain it in a stable and inactive state. At the same time, it must be able to remain in the tumour tissue and cells, and efficient release of toxin small molecules. Since toxin molecules are typically small chemical molecules with strong hydrophobicity, the linker must have good hydrophilicity to bind the toxin molecules, facilitate subsequent coupling reactions with antibodies in the aqueous phase, and avoid the formation of large amounts of protein aggregates, and cause the yield of ADC decreases. There are two common types of ADC linkers: non-cleavable linkers and cleavable linkers, each with its own characteristics. Details as follows: 1. Cleavable linkers; cleavable linkers are sensitive to the intracellular environment, and release free effector molecules and antibodies through the combined effects of catabolism and dissociation in the cell, such as acid-cleavable linkers and protease-cleavable linkers. They are usually stable in the blood, but they will quickly cleave in the low pH and protease-rich lysosomal environment to release effector molecules. In addition, if the effector molecule can cross the membrane, it can eliminate the tumor by exerting a potential bystander effect. 2. Non-cleavable linker; non-cleavable linker is a new generation of linker, which has better plasma stability than cleavable linker. Because non-cleavable linkers can provide greater stability and tolerance than cleavable linkers, these linkers reduce off-target toxicity and provide a larger therapeutic window. In recent years, through continuous improvement and optimization of these two types of linkers, various linkers have been developed that can significantly improve the stability and hydrophilicity of ADC. The linker generally includes four molecular fragments: antibody linking fragment, regulatory fragment, enzyme degradation fragment and self-cleavage fragment. Developers usually conduct comprehensive analysis and evaluation to screen the above four fragments based on the characteristics of the toxin small molecule and the way it is connected to the antibody, combined with the impact on the ADC molecule, and finally determine the structure of the linker.

Among them, Aminoethyl-SS-ethylamine is a cleavable linker. It connects two different molecules through disulfide bonds (SS). Taking ADC as an example, it can link an antibody and a drug molecule. Since disulfide bonds can be degraded under reducing conditions, and this reducing agent is generally lacking in normal physiological environments, they can be reduced in specific cells (such as tumor cells) to release their loaded payload molecules. In addition, the linker also contains an aminoethyl group, which can react with carboxyl groups, aldehyde groups or other molecular groups on the surface of biomolecules, which provides sites for further functionalization or attachment of other molecules.

Alternate Names:
N,N'-Bis(2-aminoethyl)cystamine
Cystamine dihydrochloride
2,2'-Dithiodiethanamine
Bis(2-aminoethyl) disulfide
2,2'-Dithio-bis-ethylamine

References:
1. Su Z, et al.; Antibody-drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B. 2021, 11(12):3889-3907.

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