A range of factors may contribute to the immunogenicity of therapeutic antibodies in patients but a major driver for immunogenicity is likely to be T cell help. Techniques have thus been developed that screen for MHC Class II restricted T cell epitopes in antibody variable region sequences to assess the potential for immunogenicity in therapeutic antibodies. Three such techniques are binding of peptides to human MHC Class II, binding of peptide-MHC complexes to T cell receptors, and in vitro human T cell assays. The most accurate measurement of T cell epitopes has been achieved using in vitro T cell assays, and these have demonstrated utility in testing antibodies as whole proteins as well as overlapping peptides from variable regions for the potency and location of T cell epitopes. Such in vitro T cell assays are now being used as a preclinical screen for antibody immunogenicity and for testing different formulations and manufacturing batches.

“NONSELF” ANTIBODIES

The evolution of a high affinity antibody response against an antigen in vivo is associated both with rearrangement of the variable and constant region genes as well as somatic hypermutation of the variable regions. The resultant antibody secreted by a fully differentiated B cell (plasma cell) can be considered to be immunologically “nonself” by virtue of unique non-germline mutations introduced into the variable region sequences. However, such “nonself” antibodies are tolerated by the mammalian immune systems through various mechanisms of peripheral tolerance as well as by the fact that the effective concentration of any individual antibody present in the circulation at any given time is relatively low.