Humanisation by Guided Selection

The hybridoma technology has given rise to many rodent antibodies with exquisite specificity. Unfortunately, the use of murine antibodies for immunotherapy of human carcinomas has a disadvantage that during the repeated administration of the monoclonal antibodies to patients, a human anti-mouse antibody (HAMA) immune response can be induced. This HAMA response may cause a rapid blood clearance of the monoclonal antibodies, thereby reducing its efficacy (Khazaeli et al., 1994). Murine antibodies can be humanised by CDR-grafting (Jones et al., 1986; Chapter 40) where the hypervariable loops of the monoclonal antibody are transplanted to a human antibody, thereby retaining the epitope and specificity. However, such CDR grafted antibodies retain a large proportion of non-human sequences, which include the CDR’s as well as framework residues, which are sometimes retained because they are involved (in)directly in antigen binding (Foote & Winter, 1992). Furthermore, humanisation by resurfacing (Roguska et al, 1996) yields the incorporation of even more non-human sequences. In all instances, some rodent antibody derived sequences are still included in the humanised antibody and thereby may enable the monoclonal antibody to provoke an immune response. For example, the transplantation of CDR-loops with non-human canonical forms, such as canonical structures 1 and 5 of murine light chain loop L1 for which no human homologue was found (Tomlinson et al., 1995), may both change the idiotype structure of the antibody combining surface as well as provide unique non-human T-cell epitopes.