Antibody-drug conjugates in breast cancer: advances and prospects

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Figure 1
Third-generation antibody-drug conjugates: the rationale and mechanisms. (A) After antibody-drug conjugates (ADCs) enter the bloodstream, the antibody component binds to the antigen on the surface of the target cell. The ADC is then internalized through receptor-mediated endocytosis and subsequently releases the cytotoxic payload via the endosome-lysosome pathway, killing the tumor cells. (B) Payloads with membrane permeability also exert a bystander effect, leading to the death of surrounding antigen-negative cells. (C) In the acidic environment caused by high metabolism in tumors, the ADC linker undergoes cleavage at the toxin end, releasing the payload to kill tumor cells.

Table 1

Comparison between first-, second-, and third-generation ADCs

Properties/Generation	First-generation ADCs	Second-generation ADCs	Third-generation ADCs
Antibody type	Murine or chimeric antibodies	Human-mouse chimeric antibodies, humanized monoclonal antibodies	Fully human monoclonal antibodies
Linker	Unstable	Cleavable and non-cleavable	More stable, site-specific
Cytotoxin	Lower toxicity	Higher toxicity	Various highly effective small molecule toxins
Drug-to-antibody ratio	Non-uniform	Non-uniform	Uniform
Targeting	Lower	Higher	Highest
Immunogenicity	High	Lower	Lowest
Safety	Stronger toxicity/side effects	Stronger side effects	Lower toxicity
Clinical efficacy	Poor effect	Better effect	Best effect
Clinical application	Few clinical applications	Widespread clinical application	Widespread application with significant effects
Features	Non-site-specific conjugation, short half-life	Site-specific conjugation, improved efficacy	Site-specific conjugation, wider therapeutic window