항체 약물 중합체의 항체-링커 중합 방법의 최신 동향 (Recent Trends in Conjugation Methods of Antibody Drug Conjugate)

서지정보

· 발행기관 : 대한약학회
· 수록지 정보 : 약 학 회 지 / 69권 / 1호 / 1 ~ 15페이지
· 저자명 : 임정현, 박서진, 황상수, 이주원, 조현진, 신영근

초록

Antibody-drug conjugates (ADCs) represent a promising class of targeted therapies, consisting of a monoclonal antibody linked to a potent cytotoxic payload via a chemical linker. The drug-to-antibody ratio (DAR), denoting the number of payload molecules conjugated to each antibody, is one of the most important critical quality attributes (CQAs) of ADCs, as it significantly influences the physicochemical and pharmacokinetic properties of ADCs, ultimately affecting their efficacy and safety profiles. Traditional ADC conjugation methods primarily conjugated payloads to lysine residues on the antibody surface or to free thiol cysteine residues after reducing interchain disulfide bonds. However, these methods often resulted in heterogeneous mixtures due to non-site selective conjugation and variability in DAR. Recently, to overcome these limitations, site-specific conjugation strategies have been developed to achieve homogeneous ADCs with consistent DAR values and drug loading disposition. Briefly, first-generation ADC conjugation technologies conjugated the linker-payload to natural amino acids residues commonly found in antibody structure. In contrast, second-generation technologies introduced specific amino acid modifications or additional aminoacid sequences at the DNA level to enable site-specific conjugation. Third-generation technologies enable site-specific conjugation and precise DAR control without DNA level modifications. This review explores the evolution of conjugation techniques for ADCs, highlighting advancements toward more site-specific and precise DAR control.

영어초록

Antibody-drug conjugates (ADCs) represent a promising class of targeted therapies, consisting of a monoclonal antibody linked to a potent cytotoxic payload via a chemical linker. The drug-to-antibody ratio (DAR), denoting the number of payload molecules conjugated to each antibody, is one of the most important critical quality attributes (CQAs) of ADCs, as it significantly influences the physicochemical and pharmacokinetic properties of ADCs, ultimately affecting their efficacy and safety profiles. Traditional ADC conjugation methods primarily conjugated payloads to lysine residues on the antibody surface or to free thiol cysteine residues after reducing interchain disulfide bonds. However, these methods often resulted in heterogeneous mixtures due to non-site selective conjugation and variability in DAR. Recently, to overcome these limitations, site-specific conjugation strategies have been developed to achieve homogeneous ADCs with consistent DAR values and drug loading disposition. Briefly, first-generation ADC conjugation technologies conjugated the linker-payload to natural amino acids residues commonly found in antibody structure. In contrast, second-generation technologies introduced specific amino acid modifications or additional aminoacid sequences at the DNA level to enable site-specific conjugation. Third-generation technologies enable site-specific conjugation and precise DAR control without DNA level modifications. This review explores the evolution of conjugation techniques for ADCs, highlighting advancements toward more site-specific and precise DAR control.

참고자료

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