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Review
. 2022 Dec:78:102818.
doi: 10.1016/j.copbio.2022.102818. Epub 2022 Oct 12.

Engineering the supernatural: monoclonal antibodies for challenging infectious diseases

Patricia S Grace  1 , Bronwyn M Gunn  2 , Lenette L Lu  3
Affiliations
Review

Engineering the supernatural: monoclonal antibodies for challenging infectious diseases

Patricia S Grace et al. Curr Opin Biotechnol. 2022 Dec.

Abstract

The COVID-19 pandemic demonstrated that monoclonal antibodies can be deployed faster than antimicrobials and vaccines. However, the majority of mAbs treat cancer and autoimmune diseases, whereas a minority treat infection. This is in part because targeting a single antigen by the antibody Fab domain is insufficient to stop the dynamic microbial life cycle. Thus, finding the 'right' antigens remains the focus of intense investigations. Equally important is the antibody-Fc domain that has the capacity to induce immune responses that enhance neutralization, and limit pathology and transmission. While Fc-effector functions have been less deeply studied, conceptual and technical advances reveal previously underappreciated antibody potential to combat diseases from microbes difficult to address with current diagnostics, therapeutics, and vaccines, including S. aureus, P. aeruginosa, P. falciparum, and M. tuberculosis. What is learned about engineering antibodies for these challenging organisms will enhance our approach to new and emerging infectious diseases.

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Figures

Figure 1
Figure 1
Antibodies function through the combination of the Fab and Fc domains. The antibody Fab domain recognizes extracellular microbes or infected host cells. Antibody–Fc interactions with FcR expressed on effector cells, including FcγRs and FcαR, induce a breadth of Fc-effector functions. High-affinity-activating FcRs (such as FcγRI and FcRN) bind tightly to IgG. Modulation of functions is mediated by the combinatorial engagement of the low-affinity-activating FcRs (FcγR3A, FcγR3B, and FcγR2A) and the only inhibitory FcγR2B. The various subclass, isotype, and post-translational Fc glycosylation of antibodies alter Fc–FcR interactions to modulate ADCP in DCs, macrophages, monocytes, and neutrophils; ADCC on NK cells and neutrophils; inflammatory chemokine and cytokine responses; and complement activation.
Figure 2
Figure 2
Antibodies have the potential to target a spectrum of host microbial interactions in infectious diseases. (a) Antibodies targeting key P. falciparum antigens can block infection at multiple stages of the malaria life cycle. By inhibiting liver infection, antibodies prevent sporozoite adaptation and replication within the host. Later in the P. falciparum life cycle, antibodies targeting blood-stage antigens block schizont and ring-stage infection of RBC. Finally, antibodies targeting gametocyte antigens decrease transfer of P. falciparum to the mosquito vector from the infected host. (b) Some but not all antibodies facilitate pathogen uptake to direct phagocytosed pathogens to lysosomal compartments for destruction. (c) Antibodies can bind and neutralize pathogenic toxins and virulence factors to prevent lysis of cells and tissue damage during infection. (d) Antibodies specific for antigens found within the matrix of microbial biofilms can disrupt their structure and recruit immune cells to eradicate bacteria. (e) Nebulized antibody therapy can reduce horizontal transmission of infection via aerosol. During pregnancy, antibodies can block vertical transmission to the fetus.
Figure 3
Figure 3
Diverse antibody-Fc-effector features and functions induced during natural infection have the potential to form the basis of engineering mAbs with ‘supernatural’ functions. (a) In humans, natural diversity in subclass and isotype drives distinct antibody-effector functional profiles. IgG is the predominant isotype detected at the highest level in the blood followed by IgA and IgM. All three isotypes are also detected in the lung after many different infections and vaccinations. Classical multimerization structures are shown through additional scaffolds have been described. Of the IgG subclasses, levels of IgG1>IgG2>IgG3>IgG4 in the blood with the longest hinged IgG3 having the shortest half-life but highest affinity for FcγR and complement. Further variation is observed with IgG alleles where amino acid changes influence CH3–CH3 interactions that impact stability and FcR binding along with downstream immune-effector functions. (b) Through engineering amino acid and glycosylation modifications on Fc domains, mAbs with ‘supernatural’ Fc-effector functional profiles that enhance protection without pathology can be generated. The combinatorial diversity from 80 amino acid and up to 36 glycan variants possible with the selective addition and subtraction of specific sugars provides a breadth of possibilities of antibody-effector functions (bottom key) for each antigen recognized by a mAb.
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