Antibodies

Mainly online for the references and not yet announced in updates. Many of references are relevant for the chapter Hypothesis on the Tropism of Omicron, where the possible of a changed tropism of the omicron variant and possible ADE effects are discussed.

in early work

subject to changes, to be checked

Summary

Antibodies are composed of two fragments:

• F_ab (fragment antigen binding) which determines the specific antigens recognized.
• F_c (fragment crystallizable) which determines structural properties, the kinetics and encodes instructions to the immune system.

Which antibody is produced depends on the immune stimulant and its locations.

Antibodies have direct effects by binding and thereby preventing the function (neutralizing activity) or by opsonizing the antigens for follow up handling.

• Neutralization: Antibodies can render the antigen incapable to function i.e. the antigen is neutralized. Examples:
  • an antibody to the RBD of coronavirus spikes can prevent the spike to bind to its target receptor. Antibodies with such effects are called neutralizing antibodies.
  • Antibodies can neutralized toxic enzymes [to confirm and cite].
• Instructions to the Immune System: Antibodies bound to a thing, instruct the immune system how to handle that thing. These instruction are mostly determined how and to which cellular receptors the antibody Fc fragments bind (subclass and glycosylation specific). The instructions can be phagocytosis, cellular cytotoxic effects, which cytokines to produce and complement activation.

Antibody Fragments

Antibodies have two fragments and antigen binding fraction (called F_ab for fragment antigen binding) and immune instruction fraction (called Fc for fragment crystallizable). The genes encoding the F_ab undergo somatic recombination and thereby new F_abs recognizing specific antigens are produced. The genes for the different Fc are constant throughout lifetime.

Antibody Classification and Immune Instructions

The Fc fragment determines the antibody classification: Antibodies are grouped into classes (IgG, IgA, IgM and IgE) and sometimes additionally into subclasses (e.g. IgG1, IgG2 and IgG3 for IgG antibodies). Additionally the Fc fraction can have post-translational modifications such as glycosylation.

Literature Antibody Classes and Immune System Instructions

• de Taeye “The ligands for human IgG and their effector functions.”
• [Irani] “Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases”
• [Hoepel] “IgG subclasses shape cytokine responses by human myeloid immune cells through differential metabolic reprogramming.”

IgG

In the case of IgG, there are the subclasses IgG1, IgG2, IgG3 and IgG4. Each subclass in turn can have additional modifications e.g. glycosylations. These properties determine to receptors the IgG antibody gets attached to.

IgA

IgE

Mechanisms of Action

Neutralization

[in work]

Change the Kinetics

[in work]

Antibodies can change the kinetics of bound antigens (mostly antibody class specific) i.e. how the antigen is distributed within the body. E.g. IgM clumps antigens together and to some extent IgA [to confirm and cite].

The kinetics is also changed when the antigen is phagocytosed. Phagocytosis is discussed in immune system instructions.

Immune System Instructions

References

Antibody Classes and Subclasses

Antibody Receptor mediated Effector Functions

de Taeye

de Taeye SW, Rispens T, Vidarsson G. The ligands for human IgG and their effector functions. Antibodies. 2019 Jun;8(2):30.

Irani

Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases http://dx.doi.org/10.1016/j.molimm.2015.03.255

Hoepel

Hoepel, W., Allahverdiyeva, S., Harbiye, H., de Taeye, S. W., van der Ham, A. J., de Boer, L., … & den Dunnen, J. (2020). IgG subclasses shape cytokine responses by human myeloid immune cells through differential metabolic reprogramming. The Journal of Immunology, 205(12), 3400-3407.

Refs Antibody induced Phagocytosis

Johnson

Johnson M, Stockdale L, de Haan N, Wuhrer M, Nouta J, Koeleman CA, Clarke J, Marinou S, Shakya M, Colin-Jones R, Theiss-Nyland K. Association of Antibody-dependent neutrophil phagocytosis with distinct antibody glycosylation profiles following typhoid vaccination. Frontiers in Tropical Diseases. 2021 Sep 16:25.

Antibodies in Virus Infections

van Erp

van Erp EA, Luytjes W, Ferwerda G and van Kasteren PB (2019) Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front. Immunol. 10:548. doi: 10.3389/fimmu.2019.00548

Davis

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection Davis et al., 2019, Cell 177, 1566–1582 May 30, 2019 a 2019 Elsevier Inc. https://doi.org/10.1016/j.cell.2019.04.036

References Antibodies to Tetanus Toxin

Tregoning

Tregoning JS, Clare S, Bowe F, Edwards L, Fairweather N, Qazi O, Nixon PJ, Maliga P, Dougan G, Hussell T. Protection against tetanus toxin using a plant‐based vaccine. European journal of immunology. 2005 Apr;35(4):1320-6.

Zanetti

Zanetti G, Mattarei A, Lista F, Rossetto O, Montecucco C, Pirazzini M. Novel Small Molecule Inhibitors That Prevent the Neuroparalysis of Tetanus Neurotoxin. Pharmaceuticals. 2021 Nov;14(11):1134.

Not about antibodies, just how to block tetanus toxins.

Pirazzini

Pirazzini M, Grinzato A, Corti D, Barbieri S, Leka O, Vallese F, Tonellato M, Silacci-Fregni C, Piccoli L, Kandiah E, Schiavo G. Exceptionally potent human monoclonal antibodies are effective for prophylaxis and treatment of tetanus in mice. The Journal of Clinical Investigation. 2021 Nov 15;131(22).

Description of antibodies against the tetanus toxin. The mechanism of action seems to be neutralization.

Wang

Wang Y, Wu C, Yu J, Lin S, Liu T, Zan L, Li N, Hong P, Wang X, Jia Z, Li J. Structural basis of tetanus toxin neutralization by native human monoclonal antibodies. Cell Reports. 2021 May 4;35(5):109070.

Volk

Volk WA, Bizzini B, Snyder RM, Bernhard E, Wagner RR. Neutralization of tetanus toxin by distinct monoclonal antibodies binding to multiple epitopes on the toxin molecule. Infection and immunity. 1984 Sep;45(3):604-9.