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Page 214 Wu et al. Cancer Drug Resist 2018;1:204-18 I http://dx.doi.org/10.20517/cdr.2018.16

current third generation of ADCs has significantly benefited from the engineering of IgG molecules,
which are well suited for drug conjugation and enhance the homogeneity and therapeutic index of ADCs.
Moreover, the first biparatopic ADC, MEDI-4276, targets two non-overlapping epitopes on the same HER2
antigen and can thus potentially improve drug delivery to tumours while reducing drug exposure to normal
tissue. A variety of new formats of mAbs are under investigation in pre-clinical stages, providing new
opportunities to develop antibody-dual-drug conjugates or nanobodies/single chain fragment/peptide-drug
conjugates in the future. In addition, diversification of linking strategies such as cleavable/non-cleavable
linkers and charged/non-polar linkers have been utilized in linker design to balance the need for stability
in the circulation and efficient cleavage upon delivery into tumour cells, therein enhancing or reducing
bystander effects. Several linking strategies are also under investigation to increase solubility and drug-
[3]
antibody ratio of ADCs .

Finally, patient selection strategies in the clinical study of ADCs can make the difference between success
and disappointment. The level of antigen expression on cancer cells’ surface is a key parameter in predicting
the likelihood of the amount of payload delivered to a cancer cell in a tumour. Thus, selecting patients whose
target antigen density (on their cancer cells’ surface) is above a threshold level is important to optimising
ADC activity. However, one of the challenges to meet this criterion is identifying the presence of target
antigens in real time and by minimally invasive techniques. Several strategies to develop new diagnostic tests
to assess the level of cell target antigens are under investigation. For example, 89Zr radiolabeled trastuzumab
positron emission tomography scans are able to demonstrate, in real time, HER2 expression levels with
[90]
the advantage of being relatively non-invasive . Circulating DNA can also predict HER2 status, reducing
the need for invasive biopsies. There is clearly much yet to explore in the future for biomarkers to predict
whether patients will respond to ADC treatment.

In summary, incorporating ADCs into future GI malignancy treatment offers exciting opportunity for better
outcomes for cancer patients. Future strategies will focus on optimal application of ADCs, especially in
establishing the best combination modalities for treating different GI tumours, designing new generation of
ADCs with high potency and stability as well as co-developing biomarker detection technologies for better
patient selection.

DECLARATIONS
Acknowledgement
All authors would like to acknowledge National Health Service funding to the National Institute for Health
Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of
Cancer Research.

Authors’ contributions
Wrote the manuscript: Wu X, Kilpatrick T
Edited, reviewed and approved the manuscript: Chau I

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
Chau I is on the advisory board for Eli-Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck-Serono, Five
Prime Therapeutics and Astra-Zeneca. He has received research support from Eli-Lilly, Janssen-Cilag, Sanofi