Human monoclonal antibodies for PEP

Human or Equine plasma derived polyclonal Rabies Immune Globulin (HRIG or ERIG) supplies are limited globally, hence, WHO category III exposures requiring Post-exposure Prophylaxis (PEP) are often treated with vaccine alone rather than the recommended vaccine plus RIG. This shortage has been recognized by WHO and the recommendation to make progressive switch to monoclonal antibodies (mAbs) has been confirmed. Crucell took this recommendation and started their discovery program in 2003 to develop a combination of two fully human mAbs, CR57 and CR4098. A joint development partnership with sanofi Pasteur was implemented in 2007. Each mAb is directed against a distinct non-overlapping epitope on the rabies virus (RV) glycoprotein. The mAb combination, CL184, has been developed to ensure coverage against diverse RV isolates and both components are needed to do so.

The use of human mAbs has several advantages over current standard of care, HRIGs or ERIGs. First of all, they can be produced in large quantities sufficient to meet the demand in endemic areas. Second, the mAbs can be produced in a consistent manner under highly controlled conditions. Third, they have a consistent potency with a high specific activity. Fourth, CL184 is formulated much more concentrated allowing to inject, in a higher percentage of rabies exposures, all mAbs into the wound area where the rabies virus is located as recommended by ACIP, avoiding to have to inject the remaining of the dose in a distant site.

To date, CL184 has been evaluated in healthy subjects in four different clinical trials conducted in the US, India, and the Philippines. These studies have demonstrated a good safety profile and also showed that similar serum neutralizing titers were reached in combination with rabies vaccine when compared to human RIG plus rabies vaccine. We are excited in November 2011 another Phase IIb trial in India will start with sanofi Pasteur support to generate additional safety and efficacy data on CL184. In the meantime, we are preparing for Phase III efficacy testing in individuals with confirmed exposures to assess CL184 efficacy in a human PEP setting. Data from these clinical studies will allow us to move toward licensing of CL184 and to make it available to the people in need in rabies enzootic areas.

To ensure global coverage of RV by CL184, we have implemented a wide epidemiological surveillance program. Although previously we had shown full coverage of a global panel of representative RV strains, we wanted to further expand this evaluation due to the heterogeneity in the RV glycoprotein sequence observed in natural field RV isolates. Within our surveillance network, our main areas of attention are USA, China, India, and the Philippines. For each area, we have a collaborating center that is responsible for sample collection, rabies confirmation, and RV glycoprotein sequencing. The RV glycoprotein sequence data is used in a statistical algorithm to determine representative RV isolates in a given RV sequence cluster that we then test for in vitro neutralization by CL184. For this we have developed a new assay specifically designed to assess the neutralizing capacity of CL184 against primary field RV isolates directly without any laboratory manipulations. This prevents potential introduction of mutations during virus amplification as needed for use in RFFIT. To date, we have collected close to 600 RV isolates from the different regions. The program is most advanced in the US where we have collected 200 RV and tested 74 representative RV isolates all of which were efficiently neutralized by CL184.

We anticipate this program will run at least for the next years to come to generate sufficient CL184 neutralization data against RV isolates from different areas in order to enhance the statistical certainty of global RV coverage by CL184 and detect any new RV variant that can emerge in enzootic areas.

Contributed by Dr Wilfred Marissen, Project Director of the Rabies Antibody Combination project, Crucell. There is more information on this project available on the Crucell website. The latest clinical trial data has been published in Vaccine (2008).