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Review
. 2018 Apr 9;11(2):32.
doi: 10.3390/ph11020032.

Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Affiliations
Review

Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Nirnoy Dan et al. Pharmaceuticals (Basel). .

Abstract

Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods.

Keywords: and cancer therapy; antibody; chemical linker; drug conjugation; drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Yearly peer-reviewed articles on ADCs based on PubMed search; (b) Registered clinical trials of ADCs based on Clinicaltrials.gov database; (c) Key components of an ADC.
Figure 2
Figure 2
(a) Schematic representation of ADC uptake in cells expressing target antigen followed by release of the payload; (b) Key considerations while choosing target and antibody isotype for ADC developments; and (c) subclasses of IgG.
Figure 3
Figure 3
Chemical structures of linkers used in ADCs development. (a) Key cleavable linkers: (i) Lysosomal protease sensitive Val-Cit dipeptide linker; (ii) Glutathione sensitive SPDB linker; (iii) Acid Sensitive AcBut linker; and (iv) β-Glucuronidase sensitive linker; and (b) non-cleavable linkers: (i) SMCC linker; and (ii) PEG4Mal linkers.
Figure 4
Figure 4
Chemical structures of first and second generation payloads used in ADCs. (a) 1st generation ADC payloads: (i) doxorubicin; (ii) 5-fluorouracil; and (iii) methotrexate; (b) DNA damaging agents: (i) calicheamicin γ1; (ii) duocarmycin A; and (iii) SJG-136 PDB dimer; and (c) tubulin polymerization inhibitors: (i) monomethyl auristatin E (MMAE); (ii) mertansine (DM1), monomethylauristatin F (MMAF), and ravtansine (DM4).
Figure 5
Figure 5
(a) Status of clinical trials on ADCs; (b) Different ADC payloads in clinical trials; (c) Different ADC linkers in clinical trials; (d) Clinical trials of ADCs for different type of oncologic indications based on clinicaltrials.gov database search.
Figure 6
Figure 6
Schematic diagram showing transition of ADCs from laboratory to clinic.

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