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  • Antibodies (Abs), also known as immunoglobulin (Ig), are one of the most important categories of biotherapeutic drugs for the treatment of many diseases including cancer, allergies, and autoimmune diseases. Antibodies are large biomolecules with a molecular weight of about 150kda, which consists of an antigen-binding fragment (Fab) and a crystallizable fragment (Fc). The Fab region is composed of one constant and one variable domain of each of the heavy and the light chain, and the region determines the specificity and affinity of an antibody for target antigen. The Fc region is composed of two constant heavy chains and can actively complement or bind to Fc receptors expressed on the surface of immune effector cells, thereby exerting effector functions such as complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

    Antibodies are classified into five isotypes: IgA, IgD, IgE, IgG and IgM, according to their heavy chains. Among the five isotypes, IgG is the principal isotype in the blood and extracellular fluid. IgG is also the second longest circulating protein in the blood, and the long half-life of IgG is attributed to the endocytic salvage pathway mediated by the neonatal Fc receptor (FcRn). IgG can be further divided into four subclasses including IgG1, IgG2, IgG3 and IgG4. Each subclass has unique features in terms of antigen binding, immune complex formation, complement activation, effector cell triggering, half-life, and placental transport.

    General Properties of Human IgG Subclasses

      IgG1 IgG2 IgG3 IgG4
    Molecular mass (kD) 146 146 170 146
    Amino acids in hinge region 15 12 62a 12
    Inter-heavy chain disulfide bonds 2 4b 11a 2
    Mean adult serum level (g/l) 6.98 3.8 0.51 0.56
    Relative abundance (%) 60 32 4 4
    Half-life (days) 21 21 7/∼21a 21
    Placental transfer ++++ ++ ++/++++a +++
    Antibody response to:
    Proteins ++ +/− ++ ++c
    Polysaccharides + +++ +/− +/−
    Allergens + (−) (−) ++
    Complement activation
    C1q binding ++ + +++

    a: depends on allotype. b: for A/A isomer. c: after repeated encounters with protein antigens, often allergens.
    DOI: 10.3389/fimmu.2014.00520.

    The effector functions of the four IgG subclasses are directly related to their affinity for Fc-gamma receptors (FcγRs). IgG1 and IgG3 have overall strong effector function profile. IgG3 shows high affinity binding to most FcγRs, but is not routinely selected as a therapeutic format due to its long hinge region and polymorphic nature, both of which increase the risk of stability and immunogenicity. IgG1 is the subtype most commonly used to develop therapeutic drugs because of its stability, less aggregation formation, and triggering effector functions via Fc domain binding to FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16).

    The advantage of antibodies being developed into multi-modality drugs is that they can bind to target molecules with high specificity and affinity, and they have a relatively long half-life and limited biodistribution in the human body. In addition, the half-life and biodistribution of antibodies can be adjusted by protein engineering. Antibodies can drive effective immune responses through Fc-mediated effector functions. In recent years, an increasing number of non-traditional drug modalities based on antibodies have been developed, including single-domain antibody fragments, bispecific or trispecific antibodies, antibody-drug conjugates (ADCs), etc.

    Anti-cancer ADC Drugs with Different IgG Subclasses

    ADC IgG Subclass Target Condition
    Disitamab Vedotin IgG1 kappa ERBB2; Tubulin Solid Tumor
    Loncastuximab Tesirine (Zynlonta) IgG1 kappa CD19 Leukemia; Lymphoma
    Cetuximab Sarotalocan (Akalux) IgG1 kappa ABCB1; EGFR Solid Tumor
    Tisotumab Vedotin (Tivdak) IgG1 kappa Tubulin Solid Tumor
    Polatuzumab Vedotin (Polivy) IgG1 kappa CD79b; Tubulin Leukemia; Lymphoma
    Enfortumab Vedotin (Padcev) IgG1 kappa NECTIN4; Tubulin Solid Tumor
    Inotuzumab Ozogamicin (Besponsa) IgG4 CD22 Leukemia; Lymphoma
    Ibritumomab Tiuxetan (Zevalin) IgG1 kappa MS4A1 Lymphoma
    Gemtuzumab Ozogamicin (Mylotarg) IgG4 CD33 Leukemia

    Product Range

    Amerigo Scientific offers a range of recombinant Fc proteins of different IgG subclass to facilitate IgG structure-based drug development. Our IgG Fc proteins can be used as an ideal isotype control for monoclonal antibodies, IgG-like bispecific antibodies, ADCs, and IgG FC-fusion therapeutics in screening, functional verification, and other processes.

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