![]() ![]() Among the FDA-approved 22 anti-tumor antibodies (Table 1), almost half (10) of them engage in anti-tumor activity via Fc-mediated effector functions. Anti-tumor antibody drugs exert therapeutic efficacy by several different, but not mutually exclusive, mechanisms, including (1) Fc-mediated effector functions (ADCC, ADCP, CDC) (2) blocking tumor growth signals (3) inhibiting angiogenesis (4) triggering apoptotic pathways in tumor cells (5) activating immune cells. This review outlines fundamental strategies that are required to select IgG subclasses in developing anti-tumor therapeutic antibodies.ĭue to its high specificity and superior pharmacokinetics, the antibody drug has attracted great attention across the pharmaceutical industry since the late 1990s, especially following the inaugural approval of rituximab, the first anti-tumor antibody drug, in 1997. Therefore, when developing anti-tumor therapeutic antibodies, including single-targeted antibodies, bi-specific antibodies (BsAbs), and antibody-drug conjugates (ADCs), many factors, such as target biology, cellular distribution of the targets, the environments of particular tumor types, as well as the proposed mechanism of action (MOA), must be taken into consideration. Fcγ receptors include six subtypes (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, FcγRIIIA, FcγRIIIB) which differ in cellular distribution, binding affinity to Fc, and the resulting biological activity. As a result, different subclasses have different effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Among the four subclasses of human IgG (IgG1, IgG2, IgG3, IgG4), which differ in their constant regions, particularly in their hinges and CH2 domains, IgG1 has the highest FcγR-binding affinity, followed by IgG3, IgG2, and IgG4. ![]() The intact antibody of human immunoglobulin (IgG) is composed of the fragment for antigen binding (Fab) and the crystallizable fragment (Fc) for binding of Fcγ receptors. ![]()
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