MONOCLONAL ANTIBODIES FOR HEPATITIS C VACCINATION ANDTHERAPY

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There are two distinct parts to this project:

1. Development of an antibody-based vaccine
This proposal is based on a mouse monoclonal antibody (MAb) AP33, developed in-house, that is capable of neutralizing infection by all hepatitis C virus (HCV) major genotypes and subtypes. As AP33 is a broadly neutralizing antibody recognizing a highly conserved epitope in the HCV E2 glycoprotein, this region is a target for vaccine development. Attempts using appropriate antigen fragments were not successful in eliciting antibodies against this protective epitope, indicating that designing immunogens displaying the correct presentation of the epitope will be essential for generating the desired response. To this end, we will use innovative approaches to generate such antigens and immunize animals with them. We will test whether these immunogens are capable of eliciting appropriate immune responses in immunized animals, and whether the immune sera are able to neutralize virus infection in cell culture assays.

2. Identification and development of novel antibodies with therapeutic potential
We have generated a large repertoire (approximately 1200) of mouse hybridoma lines that secrete MAbs to plasma membrane proteins of human liver origin, with the objective of using them as a means to identify putative cellular receptor(s) for HCV entry into target cells. Recent advances in cell culture infection models provide an excellent opportunity to screen this bank of anti-liver membrane MAbs for the ability to inhibit virus infection. Any inhibitory MAbs identified thus will be humanized and evaluated for their therapeutic potential. Innovative approaches will be developed to overcome possible deleterious effects that antibodies directed against a cellular target may have on the host.

Both parts of this project are founded on extensive experience of MAb development. Arvind Patel's group has ample experience of raising mono- and polyclonal antibodies to numerous viral and cellular antigens. We have developed ELISA-based assays for screening and characterizing appropriate antibodies, and pilot immunizations have already yielded promising results. Crucially, we have also generated a novel reporter cell line that will allow high throughput screening for antibodies that inhibit infection by HCV bearing envelope glycoproteins of any genotype.