How to select IgG subclasses in developing anti-tumor therapeutic antibodies

Abstract

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. 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 FcγRbinding affinity, followed by IgG3, IgG2, and IgG4. As a result, different subclasses have different effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). 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. 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. This review outlines fundamental strategies that are required to select IgG subclasses in developing anti-tumor therapeutic antibodies.

Mechanisms of hyperprogressive disease after immune checkpoint inhibitor therapy: what we (don’t) know

“…The interaction between the Fc domain of an antibody and its cognate FcR triggers a cascade of immune events stimulating phagocytic or cytotoxic cells to eradicate pathogens or infected/tumor cells through different mechanisms, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-mediated phagocytosis (ADCP) [ 87 , 89 ]. To avoid the killing of T cells that express ICs, most ICIs were developed by choosing antibody isotypes with low or significantly reduced binding to FcRs [ 90 – 92 ]. Indeed, nivolumab and pembrolizumab, anti-PD-1 antibodies, are IgG4, an isotype considered immunologically inert but that still retains the ability to bind FcγRI and FcγRIIb, activating and inhibitory FcRs, respectively [ 90 – 92 ].…”

“…To avoid the killing of T cells that express ICs, most ICIs were developed by choosing antibody isotypes with low or significantly reduced binding to FcRs [ 90 – 92 ]. Indeed, nivolumab and pembrolizumab, anti-PD-1 antibodies, are IgG4, an isotype considered immunologically inert but that still retains the ability to bind FcγRI and FcγRIIb, activating and inhibitory FcRs, respectively [ 90 – 92 ]. In this regard, it has been reported that tumor-associated macrophages (TAMs) are able to capture anti-PD-1 antibodies from the T cell membrane through FcγRIIb [ 93 ].…”

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

“…Fc region containing BsAbs mainly include Duobody( Labrijn et al 2013 ), FIT-Ig (Gong et al 2017 ), 2:2 CrossMab (Brunker et al 2016 ), mAb-Trap (J. Yu et al 2020 ) (Fig. 1 b).…”

“…This is achieved by combining a low-affinity CD47 arm with a high-affinity CD19 arm, thereby reducing the risk of unwanted CD47 blockade in healthy cells (Buatois et al 2018 ; Hatterer et al 2019 ). Similarly, IMM0306, a CD20 x CD47 BsAb developed by ImmuneOnco has achieved remarkable therapeutic effects in various tumor models and showed no binding to human erythrocytes in pre-clinical study (Yu et al 2020 ). Besides hematological malignancies, there are also BsAbs that work in a similar way to increase blockade/activation specificity in solid tumors, such as IBI322 and RO6874813 (RO7386).…”

Monoclonal Antibodies as Neurological Therapeutics

“…More specifically, the IgG2 subclass is commonly selected to neutralize soluble antigens without inducing host effector mechanisms as in the case of erenumab and fremanezumab [ 154 , 155 ]. Similarly, IgG4 such as natalizumab and galcanezumab represent an important subclass of mAbs commonly selected when the recruitment of the host effector mechanisms is not desirable [ 55 , 155 , 159 , 162 ].…”