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Non-IgG Antibody Isotypes

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Monoclonal antibody-based drugs continue to be one of the most rapidly growing classes of therapeutic molecules. At present, the majority of approved therapeutic antibodies are of the human IgG format, which can elicit immune effector functions. However, there is a wealth of functional diversity present in other isotypes and IgG subclasses that can be exploited to improve clinical safety and performance by increasing stability, reduction of adverse events, modulation of effector functions, and the engagement of two antigens by a single antibody.

IgA Antibody

IgA antibodies can be secreted either as monomers or as dimers when coupled to the J chain. IgA antibodies engage the FcαR receptor expressed in a number of myeloid-derived cells, most notably granulocytes and macrophages, and IgA antibodies have been shown to mediate more potent ADCC and ADCP activity compared to IgG1. Recent studies in animal models have demonstrated that IgA therapeutics may hold promise for cancer treatment. However, its short circulation half-life and inability to engage the activating Fcɡ receptors or elicit complement activation have discouraged the clinical application of IgA therapeutics.

IgD Antibody

IgD is the second isotype expressed on the surface of mature, naive B cells containing either a transmembrane domain or tethered to the surface with a glycosylphosphatidylinositol anchor. IgD has a long, O-linked glycosylated hinge region that is thought to impart a T-shape. It was recently suggested that the distinct hinge region of IgD renders surface IgD responsive to polyvalent antigens but not to monovalent antigens. The role of secreted IgD has been poorly characterized, and there is little evidence that the IgD isotype is under consideration as a potential therapeutic platform. However, a number of recent studies have demonstrated interesting antitumor functions mediated by IgD which suggests that further investigation of the therapeutic potential of this isotype is warranted.

IgE Antibody

Allergic diseases are inflammatory disorders that involve many types of cells and factors, including allergens, IgE, mast cells, basophils, cytokines and soluble mediators. Among them, IgE plays a vital role in the development of acute allergic reactions and chronic inflammatory allergic diseases, making its control particularly important in the treatment of IgE-mediated allergic diseases. A number of drugs based on IgE-targeted therapy have been approved by the FAD and are expected to become the therapy for IgE-mediated allergic diseases.

IgM Antibody

IgM is the first isotype expressed on the surface of B cells and is also the first isotype secreted after antigenic challenge in vivo. IgM antibodies typically have low monovalent affinity but because of their pentameric or hexameric structure, they display high binding avidity. The pentameric IgM can bind to the polymeric Ig receptor present on epithelial cells, which facilitates transcytosis of IgM to mucosal surfaces. Whereas pentameric IgM can activate complement, the hexameric form activates complement about 3 times more efficiently. Although some early therapeutic candidates were of the IgM isotype (e.g., the anti-lipid A mAb, HA-1A), a lack of efficacy resulted in discontinuation of clinical trials. To date, there are no approved mAb therapeutics of the IgM isotype, although preclinical evaluation of IgM antibodies is being investigated.

Schematic overview of the five different antibody isotypes produced by B cells.Fig 1. Schematic overview of the five different antibody isotypes produced by B cells. (Killie, 2010)

IgY Antibody

IgY is the major antibody produced by chickens. IgY possesses numerous advantages over mammalian IgG in terms of high yield, low cost and convenience eventually garnering greater consideration over its mammalian counterpart. Naturally, IgY is deposited in the egg yolk for protecting their offspring from dreadful pathogens. IgY has unique properties which are being explored in different aspects for its application in research, diagnosis and therapy. Since then, the development of antibody production in avian system, numerous IgYs have been developed against diversified antigens including various parasites.

Structural of chicken egg yolk antibody (IgY) and its recombinant scFv fragment structures.Fig 2. Structural of chicken egg yolk antibody (IgY) and its recombinant scFv fragment structures. (Somasundaram, 2020)

Bovine Ultralong CDR H3

The underlying structure and diversity mechanisms driving humoral immunity are not entirely evolutionarily conserved across vertebrate species. Cows have evolved an ultralong CDR H3 that protrudes far from the typical antibody binding site. By creating structural diversity within ultralong CDR H3s encoded only by a single VHBUL, DH2, and JH paired with a limited number of lambda light chains, cattle tremendously expand their limited combinatorial repertoire. It is tempting to speculate about the evolutionary purpose for developing this unique humoral immune system. Cows are capable of mounting a very robust immune response to infectious agents.

Comparison of normal and ultralong CDR H3 antibody fab fragments.Fig 3. Comparison of normal and ultralong CDR H3 antibody fab fragments. (Haakenson, 2018)

Other Non-IgG Antibodies

Due to the diversity of species, there are also some unique antibody subtypes in individual species. In addition, the production of customized Non-IgG antibodies through genetic engineering is also very popular.

Creative Biolabs is a global biotechnology services company that has been developing antibodies for many years. With PhD-level researchers and state-of-the-art facilities, we offer a comprehensive range of customized antibodies and related services in a timely and cost-effective manner to meet your specific needs. If you have any questions about our services, please contact us and we will provide you with a detailed explanation.


  1. Killie, Ida. Development of new tissue culture protocols for enrichment of CD4 T cells associated with neonatal alloimmune thrombocytopenia. Master Thesis, University of Troms. 2010.
  2. Somasundaram, R., et al. An approach towards development of monoclonal IgY antibodies against SARS CoV-2 spike protein (S) using phage display method: A review. International immunopharmacology. 2020, 85: 106654.
  3. Haakenson, J. K., et al. Diversity in the Cow Ultralong CDR H3 Antibody Repertoire. Frontiers in immunology. 2018, 9: 1262.

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