Infectious diseases

One of the hall marks of infectious entities is that they often can escape the (human) immune system, a striking example for this is HIV-1. This virus not just invades the human defense system, but it has also evolved a set of strategies to escape that system. The problems to develop a vaccine for HIV demonstrate this point. The group of Prof Verrips has been asked to join one of the Bill & Melinda Gates projects on HIV, headed by Prof R. Weiss of UCL to explore the possibility to combat HIV with llama antibodies. To the surprise of many scientists, raising antibodies [more accurately VHH] that broadly neutralize even resistant HIV variants proved to be quite successful. This is demonstrated in Fig 1 and 2.

Fig. 1 shows the diversity of the selected anti HIV from a number of immunizations, whereas Fig 2 shows the various epitopes on the env. trimer of HIV that are recognized by the selected VHH. This figure was the result using various techniques like X-ray determination of 3D structures, molecular modelling, competition assays and epitope masking and mapping (Strokappe, 2012).  The best VHH, J3 neutralizes over 94% of the broad panel of tested HIV strains. Whereas most of the VHH against HIV have been selected using binding studies, J3 has been selected by direct neutralization studies (McCoy et al 2012). Recently J3 has been tested as microbicide in a macaque trial and the results of this trial confirm that highly effective VHH can be selected against this infectious entity. (yet to be published)

Fig.1 The diversity of anti-HIV VHH obtained by immunization of two different gp140 HIV enveloped proteins after prolonged immunization of one lama
Fig. 2 Epitopes on trimeric spike of HIV as recognized by four different groups of VHH

Many more studies have been performed by various groups related to QVQ to select VHH against infectious particles and without any exception the selected VHH perform quite well in detection the infectious entities as well in neutralizing them. It all started with an attempt to combat infections of animals, without using antibiotics. At that occasion also the special property of many lama antibodies that they recognize “hidden” epitopes was found (Muyldermans S. 2013).  Subsequently this was followed with the discovery that anti-rota virus VHH neutralize this virus quite well (v.d. Vaart, et al. 2002).  Another nice example carried out on behalf of Ablynx b.v, was the selection against RSV, H5N1 and Rabies (Hultberg et al. 2011), but also VHH against infectious entities different from viruses have been selected, like VHH against TSST (Adams, et al. 2009), LPS (El Khattabi et al. 2006), OMP and Flippase. The most recent example of the potential of VHH to combat infectious entities is the protecting effect of VHH against Clostridium difficile toxin B shown in a study using VHH immobilized on the surface of lactic acid bacteria (Andersen et al. 2015).