CD40 is an important antigen involved in immune regulation and anti-CD40 antibody therapies against human CD40 expressing tumours may be particularly advantageous. The antibody could induce tumour response in two ways. Firstly it might have a direct anti-tumour effect and secondly it could 'boost' the immune system to provide a heightened immune response that evades tumour tolerance. This project has explored the effects of CD40 ligation of a variety of CD40 expressing tumours including transformed human B cell lines (RL and Daudi), human epithelial cell lines (MG79 [ovarian] and Caski [cervical]) and primary human B cell non-Hodgkin's lymphomas obtained, with consent, from patients undergoing excision lymph node biopsy or splenectomy. The ligation of CD40, on transformed human B cell lines, using chinese hamster ovary cells transfected to express human CD40L and human soluble CD40L has shown significant cellular growth inhibition (p<O.001). Ligation of CD40 on human epithelial cell lines using human soluble CD40L has also resulted in significant growth inhibition. In primary B cell human non-Hodgkin's lymphomas ligation of CD40 with both CD40L expressing CHO cells and human soluble CD40L in the presence of human IL4 has caused significant cellular proliferation (p<O.001) and induced upregulation of cell surface and costimulatory molecules including CD80, CD86, CD58, CD54. Anti-tumour activity has been identified in a xenograft model of a transformed human B cell line (Daudi) treated with both a mouse anti-human CD40 antibody and a chimeric human anti-CD40 antibody. I have performed important preclinical toxicology studies testing mouse anti -CD40 (3/23) by injecting the antibody intraperitoneally or intravenously in to BALB/c mice. The mice have been culled following treatment and a reversible dose dependent transaminitis associated with microscopic evidence of a reversible Iympho-granulomatous hepatitis, that at the highest dose levels is acutely necrotising, has been identified. These antiCD40 antibody toxicology studies are essential before a protocol for a phase I trial of human anti-CD40 antibody against CD40 expressing human tumours is developed. I have developed a new chimeric human anti -CD40 antibody containing human constant regions and mouse variable regions. This antibody is currently undergoing large scale production for a proposed trial to treat patients with CD40 expressing tumours (excluding low-grade non-Hodgkin's lymphoma) who have failed conventional therapies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:274432 |
| Date | January 2002 |
| Creators | Harvey, Melanie Louise |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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