Amino Acids for Synthesis of Antibody-Drug Conjugates (ADCs)

Among natural amino acids, only lysine and cysteine can be used to synthesize anti-drug conjugates (ADCs). Unnatural amino acids can be constructed into recombinant proteins to obtain residue side chains that can react with small molecule drugs.

Introduction

ADCs connect small molecule drugs with biological activity to monoclonal antibody through a chemical link, and monoclonal antibodies serve as carriers to transport small molecule drugs to target cells.

Antibody-Drug Conjugates (ADCs)

• Natural amino acids

Traditional ADCs use the amino group of antibody lysine or the sulfhydryl group of cysteine obtained by opening the disulfide bond between chains to couple. The amino group of lysine and the activated carboxylate linker are connected by amide bond, and the sulfhydryl group of cysteine reacts with the maleimide group. An antibody molecule contains 80 ~ 90 lysines, and coupling may occur on nearly 40 different lysine residues. Opening the disulfide bond between the chains will result in multiple cysteine residues, and the integrity of the antibody molecule will be destroyed. Therefore, the traditional ADC is a highly heterogeneous mixture with poor homogeneity and low stability, affecting the efficacy and therapeutic window.

• Unnatural amino acids

Unnatural amino acids provide a new technical means for the development of ADC. Antibody drug site-specific coupling can be achieved through unnatural amino acids. The synthesis of proteins on ribosomes is carried out through the recognition of tRNA anticodon and mRNA codon. tRNA introduced that can specifically recognize unnatural amino acids and the corresponding aminoacyl tRNA synthetase. Under the action of aminoacyl tRNA synthetase, tRNA and the corresponding unnatural amino acids combine to form aminoacyl tRNA, and then complement the codon on mRNA through its anticodon, so that the unnatural amino acids are integrated into the polypeptide chain to synthesize a recombinant antibody containing unnatural amino acids.

The unnatural amino acids introduced are usually acetylphenylalanine, azido methyl-l-phenylalanine and azido lysine. The ketone and azido functional groups on the unnatural amino acids can react with the drug linker to obtain an ADC with uniform drug to antibody ratio. Keto group can form oxime bond with hydroxylamine group, azide group can form cycloaddition reaction of 1,2,3-triazole with alkynyl group under the catalysis of copper, and azide group can also combine with cyclooctyne without the catalysis of copper to generate azide octyne cycloaddition reaction.

View Our List of Unnatural Amino Acids >

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