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Page 2 of 13 Yagishita et al. J Cancer Metastasis Treat 2019;5:75 I http://dx.doi.org/10.20517/2394-4722.2019.026

INTRODUCTION
An antibody is a humoral immunity factor produced by B cells as a biological defense against foreign
antigens in the living body. Antibodies, i.e., immunoglobulins, are composed of a light chain and a heavy
[1]
chain, and there are 2 types of light chains and five types of heavy chains . Immunoglobulins are classified
into IgA, IgD, IgE, IgG, and IgM according to heavy chain subtypes, and in human organisms, IgG accounts
for 80%. The IgG family includes IgG1, IgG2, IgG3, and IgG4 according to heavy chain subtypes. On the
other hand, immunoglobulin receptors are expressed on neutrophils and macrophages and are composed
of glycoproteins called Fc receptors. The Fc receptor has subtypes depending on the immunoglobulin to be
bound, IgA binds to Fca receptor, IgD binds to Fcd receptor, IgE binds to Fce receptor, and IgG binds to
Fcg receptor. The structure of the heavy chain of IgG differs in its binding affinity to Fcg receptors, resulting
in specific functional properties for each IgG antibody subtype.

For the immunoglobulin function, four major types of mode of action are known: (1) the neutralizing
function by binding of antibody to the antigen; (2) the function of opening the cell membrane by activating
complement [complement-derived cellular cytotoxicity (CDC)]; (3) the opsonizing effect taken up by
phagocytes through binding of antibody to the antigen; and (4) antibody-dependent cellular cytotoxicity
(ADCC) that occurs by binding the antibody to NK cells and releasing cytokines. All currently approved
antibody drugs are of the IgG subtype and produce their antitumor effects through these functions.

The application of antibodies to cancer treatment was proposed by the bacteriologist Paul Ehrlich around
1900, but their clinical application became practical since the discovery of monoclonal antibody production
[2]
technology by the hybridoma of Köhler and Milstein in 1975. Monoclonal antibodies are characterized by
having high antigen specificity, producing almost infinite antibodies by hybridomas, and carrying out the
same analysis by producing the same antibodies. They also have advantages for anticancer treatment, such
as a long half-life, high potency, and low off-target effect.

As a result, monoclonal antibody therapy has increased hope as a “magic bullet”. However, the initial
development of monoclonal antibodies using mice or rats has been abandoned one after another because of
their short half-lives and high immunogenicity. With such a background, several techniques for modifying
antibody formulations have been developed such as chimeric antibody that genetically substitutes
the highly antigenic constant region of mouse antibody, humanized antibody that substitutes human
immunoglobulin except for the complementary-determining region (CDR) site, and fully humanized
antibody. Currently, about 26 antibody drugs have been approved against cancer, and the monoclonal
antibodies for cancer treatment will be reviewed from a pharmacogenomic perspective.

CANCER THERAPEUTIC ANTIBODY
As of August 2019, a total of 26 antibody drugs have been approved for cancer treatment by the US Food
and Drug Administration (FDA) [Table 1].

The antitumor efficacy of antibody drugs is brought about by any of the 4 functions mentioned above.
Of the 26 FDA-approved drugs, 20 are IgG1, one is IgG2, five are IgG4 isotype, and there are no drugs of
IgG3 isotype. This is considered to be due to the fact that IgG1, 2, and 4 have a half-life of about 21 days,
while IgG3 has a short 7-day half-life. The main features of each IgG subtype are shown in Table 2. ADCC
activity, which is dependent on the avidity of IgG and FcgR, is strongest in IgG3, moderate in IgG1, and
[3]
weak in IgG2 and IgG4 . Therefore, a drug that exerts ADCC activity is composed of an IgG1 isotype and
an IgG4 or IgG2 isotype for the purpose of neutralizing action or signal inhibition.

Many of the antibody drugs that have been marketed are made to have ADCC activity or ADCC activity
and a neutralizing effect as their main antitumor effects. In the 2010s, development of antibody-drug