Robert Huber

Immunreceptors-Antibody Interactions, a Structural Basis


Abstract

The immune response depends on the binding of opsonized antigens to cellular Fc receptors and the following initiation of cellular effector functions of the immune system. The crystal structures of a soluble Fcgamma receptor, an Fc fragment, and their complex explain a wealth of functional data of the system.
They also provide a rationale for the modulation of effector activities by changes of the domain arrangement of the Fc fragment caused by altered glycosylation. Myelin oligodendrocyte glycoprotein (MOG) is a major autoantigen in multiple sclerosis. The crystal structures of MOG and its complex with a specific autoantibody provide a basis for new diagnostic and therapeutic strategies against the pathogenic autoantibody response to MOG.
These molecular structures offer multiple ways to interfere with the cellular immune response in autoimmune diseases:


a) by small molecules disrupting the Fc receptor-Fc contact;
b) by antibodies directed against the contact area;
c) by soluble Fc receptors as antagonists;
d) by mimeticsof the MOG epitop.

Animal experiments following strategies b) and c) have been successfully completed for three model autoimmune diseases, SLE, arthritis, and EAE.

A company SUPPREMOL has been founded to pursue these strategies on a commercial basis and has obtained licences from the Max-Planck-Gesellschaft. Financing has been secured by a partnership with Z-cube, the Zambon Group (Milano, Italy ) corporate venture capital arm.

Sondermann, P., Huber, R., Oosthuizen, V. and Jacob, U.
The 3.2-Å crystal structure of the human IgG1 Fc fragment-FcRIII complex.
(2000) Nature 406: p. 267-273.

Krapp, S., Mimura, Y., Jefferis, R., Huber, R. and Sondermann, P.
Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity.
(2003) J. Mol. Biol. 325: p. 979-989.

Breithaupt, C., Schubart, A., Zander, H., Skerra, A., Huber, R., Linington, C. and Jacob, U.
Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein.
(2003) Proc. Natl. Acad. Sci. USA 100: p. 9446-9451.


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