Accelerating antibody discovery using transgenic animals overexpressing the neonatal Fc receptor as a result of augmented humoral immunity

  • Judit Cervenak, Roland Kurrle, Imre Kacskovics
  • Immunological Reviews, October 2015, Wiley
  • DOI: 10.1111/imr.12364

FcRn overexpression accelerates antibody discovery

What is it about?

In recent years, there has been an increasing demand for the development of faster and more efficient technologies for the generation of monoclonal antibodies against challenging targets that are weakly immunogenic or available only in limited amounts. Typical classes of such targets are cell surface antigens such as G-protein related receptors (GPCRs) or ion channels. We have developed transgenic (Tg) mice and rabbits that overexpress the neonatal Fc receptor (FcRn), resulting in an augmented humoral immune response even if challenging antigens are used for immunization. The impressively enhanced FcRn-mediated immune reactions are characterized by improved IgG protection and enhanced antigen presentation leading to greater number of antigen-specific T-helper and B-cell activation in lymphoid organs. Notably, these animals do not show any sign of autoimmunity and can be efficiently bred. FcRn overexpression thus leads to a number of practical benefits for improved generation of monoclonal and polyclonal antibodies against multiple antigens, including weakly immunogenic epitopes or tiny amounts of proteins. This review summarizes our current understanding about the mechanisms by which FcRn overexpression leads to such a significantly enhanced humoral immune response.

Perspectives

Professor Imre Kacskovics
Eotvos Lorand Tudomanyegyetem

The article highlights that we now have a better understanding of the mechanism of action for the improved immune response observed in transgenic mice and rabbits that overexpress FcRn. In particular: • At the beginning of the secondary response when the switch from IgM to IgG is occurring, the overexpressed FcRn provides better IgG protection in endothelial and hemopoietic cells leading to higher levels of circulating antigen-specific IgG. • The elevated IgG levels lead, in turn, to higher levels of antigen-IgG immune complexes that have an enhancing effect on immune responses at the level of immune complex transport into lymphoid organs and antigen presenting cell activation via their Fc gamma receptors. • In addition, and independently, FcRn expressed in antigen presenting cells facilitates more efficient transport of antigen-IgG immune complex into lysosomes. Together, these factors combine to augment the humoral immune response, allowing for the generation of a more diverse population of antigen-specific antibodies and a strong immune response even with weakly immunogenic or small amounts of antigens. This data reinforces our previous observation that our Tg mice and rabbits provide a significant advantage for researchers working with challenging antigens.

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http://dx.doi.org/10.1111/imr.12364

The following have contributed to this page: Professor Imre Kacskovics