{"id":1908,"date":"2023-06-29T22:10:43","date_gmt":"2023-06-30T03:10:43","guid":{"rendered":"http:\/\/www.creative-biolabs.com\/blog\/?p=1908"},"modified":"2023-06-29T22:10:43","modified_gmt":"2023-06-30T03:10:43","slug":"monoclonal-antibodies-how-to-choose-an-igg-subtype","status":"publish","type":"post","link":"https:\/\/www.creative-biolabs.com\/blog\/index.php\/monoclonal-antibodies-how-to-choose-an-igg-subtype\/","title":{"rendered":"Monoclonal Antibodies: How to Choose an IgG Subtype"},"content":{"rendered":"

Introduction to antibody structure and function<\/strong><\/p>\n

An antibody molecule composes of an antigen-binding fragment (Fab) and a crystallizable fragment (Fc), forming a Y-shaped structure. The Fab region is a mixed light and heavy chain dimer composed of variable light chain (VL), constant light chain (CL), variable heavy chain (VH), and constant heavy chain 1 (CH1) segments. The Fc region is a heavy chain dimer composed of constant heavy chain 2 (CH2) and constant heavy chain 3 (CH3) fragments.<\/p>\n

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Figure 1. The structure of an antibody (Chang Yang, 2023)<\/p>\n

The Fab region determines the specificity and affinity of an antibody for its target antigen. The Fc region can actively supplement or bind to Fc receptors (FcRs) on the surface of immune effector cells, thereby exerting antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis ( ADCP), and other antibody effector functions.<\/p>\n

Antibody-mediated ADCC activity is affected by factors such as tumor target expression abundance, FcR genotype, and the number of effector cells in tumor tissue. If the number of target molecules expressed per cell is less than 104<\/sup>, it is not enough to induce ADCC activity, and only when the number of molecules reaches 105<\/sup>\u2013106<\/sup> can strong ADCC activity be induced.<\/p>\n

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Figure 2. Antibody-dependent effector functions(Anupama Samantasinghar, 2023)<\/p>\n

What is the difference between the four subtypes of IgG?<\/strong><\/p>\n

Human IgG<\/span><\/strong><\/a> includes IgG1, IgG2, IgG3, and IgG4. Although all isoforms share more than 90% identity at the amino acid level, each isoform has unique properties in terms of hinge region length, number of interchain disulfide bonds, and Fc effector function. IgG1 has the highest affinity with Fc\u03b3R and has the strongest ADCC effect, followed by IgG3, IgG2, and IgG4, respectively. Fc\u03b3Rs include six subtypes (Fc\u03b3RI, Fc\u03b3RIIA, Fc\u03b3RIIB, Fc\u03b3RIIC, Fc\u03b3RIIIA, and Fc\u03b3RIIIB), which differ in their cellular distribution and affinity for Fc and the resulting biological activity. Except for Fc\u03b3RI, which is an activating receptor with high affinity for IgG and can be activated by monomeric IgG, all other Fc\u03b3Rs can be functionally activated by the Fc region of IgG only when in contact with specific antigen complexes. Fc\u03b3RIIB is the only inhibitory Fc\u03b3R. Among all Fc\u03b3R subclasses, Fc\u03b3RIIIA is mainly expressed in NK cells, so it mainly mediates ADCC, and Fc\u03b3RIIA is mainly expressed in macrophages, which mainly mediates ADCP.<\/p>\n

Selection of IgG subtype\u2014single-target antibody<\/strong><\/p>\n

Single-target anti-tumor antibodies have always been popular. Although there is no strict standard for the selection of IgG subtypes of single-target antibodies, the cellular distribution and biological functions of the target should be considered.<\/p>\n

IgG selection targeting tumor cells<\/strong><\/p>\n

When the target is an antigen on tumor cells, IgG1 should be the preferred antibody as it has a higher affinity for activating Fc\u03b3Rs and can produce strong ADCC and\/or ADCP activity on tumor cells. When ADCP function is activated, effector cells (macrophages or dendritic cells) can present processed tumor antigens to T cells, thereby further triggering tumor-specific immunity. Most of the anti-tumor antibody drugs approved by the FDA have chosen the IgG1 type. This class of drugs can block tumor growth signals (EGFR), inhibit angiogenesis (VEGFR), activate immune cells (PD-L1), and at the same time kill and eliminate tumor cells through ADCC\/CDC, thereby further enhancing the anti-tumor effect.<\/p>\n

IgG selection targeting immune cells<\/strong><\/p>\n

The selection of anti-tumor IgG subtypes targeting immune cells is more complicated, and some targets transmit inhibitory\/promotive signals to immune cells to regulate immune functions. These inhibitory signals are collectively called inhibitory receptors (such as CTLA-4, PD-1, TIM-3, and LAG-3), and promoting signals (4-1BB, CD40, OX40, CD27, GITR, etc.) are called immunostimulatory receptors.<\/p>\n