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Page 8 of 13 Yagishita et al. J Cancer Metastasis Treat 2019;5:75 I http://dx.doi.org/10.20517/2394-4722.2019.026

tumors with MMRds exhibiting micro-satellite instability (MSI), showing a robust efficacy regardless of the
type of cancer [45,46] . From these results, nivolumab and pembrolizumab were first approved by the FDA in
2017 with the genotype MSI-positive regardless of cancer type.

The HLA genotype is important as a host element. HLA class I is rich in sequence diversity of peptide
binding sites. The HLA-I allele is encoded by three genes on chromosome 6 (HLA A, HLA B, and HLA C),
[47]
and each of these variants constitutes a slightly different peptide. Chowell et al. examined the genotype
of HLA-I in 1535 patients treated with ICIs. They found that patients with HLA-B44 supertype showed
prolonged survival, and patients with HLA-B62 supertype or somatic loss of heterozygosity at HLA-I
[48]
[48]
showed reduced survival . Chowell et al. analyzed the expression of MHC class I and II in tumor
tissues in malignant melanoma treated with ipilimumab, nivolumab, or their combination. They found that
78 of 181 cases (43%) showed disappearance of MHC class I, which was correlated with initial tolerance of
ipilimumab. In addition, MHC class II expression was observed in 55 of 181 cases (30%), and a correlation
[48]
with the therapeutic effect of nivolumab was demonstrated .

As described above, several pharmacogenomic factors on the tumor side and host side are attracting
attention as ICI efficacy biomarkers. It is difficult to establish a single biomarker for ICIs because there
are multiple factors, such as blocking efficiency of the signal pathway and immune environment, on the
host side. In particular, the host immune system is considered to be a large factor, and identification of a
pharmacogenomic factor that is an index of host immune responsiveness is required.

Antibody-drug conjugate
Currently, antibody-antibody drugs (ADCs), which are obtained by linking a cytotoxic anticancer drug
(called “payload”) to the antibody with a linker, have rapidly developed as a new antibody treatment
strategy against cancer. The ADC is an innovative drug design approach that increases the local
concentration of payload only around the target due to the high target selectivity of antibody drugs (called
“bystander effect”). Drugs such as KS1/4-methotrexate and BR96-doxorubicin were developed as the first-
generation ADCs in the 1980s, but their efficacy was not satisfactory [49,50] . This may be due to insufficient
titer of the drug itself, wrong target antigen selection, poor internalization efficiency of the antibody,
poor tumor accumulation, linker stability too high/low, and immune response to mouse antibodies.
Gemtuzumab ozogamicin, an anti-CD33 ADC, received FDA approval for the first time as an ADC product
[51]
in 2000 . However, subsequent clinical trials found no clinical effect and increased fatal adverse events,
and approval was withdrawn [52,53] .

In order to overcome the challenges of first-generation ADCs, appropriate target search and appropriate
payload development are underway, and brentuximab vedotin (anti-CD30 ADC), ado-trastuzumab
emtansine (anti-HER2 ADC), and inotuzumab ozogamicin (anti-CD22 ADC) were approved by the
[54]
FDA as second-generation ADCs . However, the second-generation ADCs also have problems such as
the presence of a few unbound types due to the instability of the linker, early clearance by becoming a
free drug, and causing off-target toxicities. The development of these first- and second-generation ADCs
showed that selections of appropriate tumor cell targets, payloads, antibodies, linkers, and payload binding
sites were important points in drug discovery. In other words, if the appropriate target and an antibody
with high binding power cannot be selected, the accumulation of ADC in the tumor will be reduced; if
effective payload selection cannot be performed, sufficient cell killing effects cannot be achieved; if the
stability of the linker is low, it will dissociate in the body and cause an off-target effect; and if the stability of
the linker is too high, an effective bystander effect cannot be attained.

Based on the above, many third-generation ADC products are currently being developed [Table 4]. In
particular, in June 2019, the FDA approved Genentech’s anti-CD79b ADC, polatuzumab vedotin (Polivy),