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© Pierre Lafaye
Astrocytes marqués par des anticorps VHH anti-GFAP. Des anticorps d'alpagas dirigés contre une protéine spécifique des astrocytes, la GFAP (Glial Fibrillary Acidic Protein), ont été obtenus à partir de camélidés immunisés. La partie VHH (partie de l'anticorps qui reconnaît l'antigène) a été exprimée sous forme recombinante chez Escherichia coli.

About

The Platform was created about 30 years ago to provide murine monoclonal antibodies (mAb) to the pasteurian community. Since 2016, our activities are now focused on camel homodimeric antibodies (VHH).

Homodimeric antibodies, for which we have developed an extended expertise over the past years, may represent an alternative to conventional mAbs.

Hamers-Casterman et al (Nature, 1993, 363, 446-448) have demonstrated that in camelidae (camels, dromedaries, llamas and alpacas) about 50 % of IgG are antibodies devoid of light chains. These antibodies interact with the antigen by the virtue of only one single variable domain, referred to as nanobodiesTM or VHH. Despite the absence of light chain, these homodimeric antibodies are fully functional and exhibit a broad antigen-binding repertoire. These antibodies are also characterized by the lack of the first constant domain (CH1). This allows to differentiate homodimeric antibodies from conventional antibodies.

Methods, such as phage display, have been described to select antigen specific VHH from the VHH repertoire of immunized camels or llamas. The recombinant VHHs have a number of advantages compared with the conventional antibody fragments (Fab or scFv), because only one domain has to be cloned and because these VHHs are well expressed, highly soluble in aqueous environments and are stable at high temperature.

We have already demonstrated that VHHs directed against Glial Fibrillary Acidic Protein (GFAP), a specific marker of astrocytes, have a basic isoelectric point (pI) that confers them the ability to readily cross the BBB in vivo. In addition, due do their intrinsic stability, they bind to GFAP expressed in the cytoplasm of astrocytes (Li et al, Faseb J. 2012 26(10), 3969-3979). Recently, we have raised VHHs directed against intra-cerebral amyloid plaques and intra-neuronal neurofibrillary tangles (NFTs), the two main lesions of Alzheimer disease (AD). These VHHs have been tested in vivo in two mouse models of AD after labeling with a green fluorochrome. Following intravenous injection, we have shown by two-photon microscopy that they crossed the BBB and bind to amyloid plaques and NFTs in vivo (Li et al, Journal of Controlled Release 2016 243, 1-10). All these experiments have shown that VHHs against intra-cerebral targets and which possess a basic pI are able to cross the BBB in vivo. These findings constitute a strong evidence that VHHs are an alternative to conventional antibodies to facilitate BBB passage and to target intracellular antigens.

These properties are feeding an increasing demand for VHHs. To develop this activity, we have decided that PFIA will focus entirely on VHHs and will not sustain the mAb activity.

 

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Pierre Lafaye
Head of Antibody Engineering Platform
Phone: 01 40 61 39 20
 
25-28 Rue du Docteur Roux
75015, Paris – France