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Page 10 of 13 Yagishita et al. J Cancer Metastasis Treat 2019;5:75 I http://dx.doi.org/10.20517/23944722.2019.026

the drug-antibody ratio, the stability of the linker, and the cancer cell specificity, which have been issues
with ADCs. In addition to the development of ADCs alone, their combination with ICIs is being actively
developed.

Although it is expected that there will be a wider range of options for antibody therapy, the
pharmacogenomic factors in ADCs are not clear so far. Since the antibody part is IgG1 in many
ADCs, the above-mentioned FcgR polymorphism may have an effect. There is also concern about the
effects of metabolic and excretory enzymes in the payload. For example, there are reports that ABCC1
overexpression is involved in drug resistance to trastuzumab emtanisine, and that ABCB1 is associated with
the efficacy of gemtuzumab ozogamicin [58,59] . In addition, MMAE, frequently used as a payload in many
ADCs, is a CYP3A4 substrate, and eribulin is also a CYP3A4 substrate and an ABCB1 substrate. In other
words, classical pharmacogenomic factors such as ABC transporter and CYP may affect metabolism and
excretion of payloads and thus drug efficacy even in ADCs.

Moreover, recent ADC adverse events in clinical trials raise new concerns about immunogenicity. It
has been reported that Ds8201a has a high incidence of pneumonitis, and this was the same case with
[60]
Morab-202, which showed pneumonitis in 3 of 19 cases (15.8%) . Since the frequency of pneumonitis
is not high with antibody drugs alone, pneumonitis may be a characteristic adverse event of ADCs. It is
desirable to examine the pharmacogenomic factors of ADCs that are expected to be used more frequently
in the future, including the enhancement of immunogenicity due to the linkage between linker and
payload, and the possibility of affecting the responsiveness of host immunity.

As described above, ADCs have developed rapidly in recent years, but pharmacogenomic factors have
not been fully studied. In addition to analyzing classical ABC transporters and CYP polymorphisms,
pharmacogenomic analyses including host factors for characteristic adverse events such as lung injury are
greatly needed.

FUTURE DIRECTION OF RESEARCH
There are still many black boxes in the pharmacokinetics of antibody drugs. Despite confirming doses
several tens of times for the target occupancy in preclinical research, antibody blood concentrations in
clinical practice may vary widely. Until now, it has been said that the pharmacokinetics of antibody drugs
are not related to renal function, liver function or metabolic pathway, however, increased catabolism
associated with organ dysfunction may affect the pharmacokinetics of antibody drugs. Furthermore,
it is not clear whether the blood concentration of antibody drugs is correlated with the intratumoral
concentration. It is necessary to identify the detailed pharmacokinetics of antibody drugs and the factors
that affect the pharmacokinetics.

Another issue that must be considered is biosimilars. Unlike generic drugs, biosimilars cannot prove
the identity of active ingredients. Therefore, at the time of approval, structural similarity is shown in a
comparative quality study, PD and toxicity are shown in a comparative preclinical study, and PK, safety
and efficacy are confirmed in a comparative clinical study. However, comparative clinical trials are only
specifically designed to rule out clinically relevant differences in safety or efficacy between the biosimilar
and the reference medicine, and to confirm biosimilarity. Differences in sugar chain modification and
activity between lots have also been pointed out in the previous products, and it is still unclear whether
[61]
biosimilars can exhibit sufficient pharmacokinetics and antitumor effects in clinical practice . In addition,
it will be necessary to verify immunogenicity and pharmacogenomic differences.