Fig. 16.7 Monoclonal antibodies used to treat human diseases can be engineered to decrease immunogenicity but maintain their antigen specificity. Antibodies that are derived fully from mice, named with the suffix -omab, are immunogenic in humans. This causes patients to generate antibodies against them, limiting their usefulness over time. This immunogenicity can be reduced by making chimeric antibodies in which the V regions from the mouse are spliced onto human antibody constant regions; such antibodies are named with the suffix -ximab. Humanization is the process of splicing in just the complementarity-determining regions from the mouse antibody, further reducing immunogenicity; humanized antibodies are named with the suffix -zumab. New techniques now allow fully human (-umab) monoclonal antibodies to be derived, which are the least immunogenic type of antibody currently used for treating humans.
immune responses (Fig. 16.7). Genetically engineered mice that harbor human immunoglobulin genes inserted into their immunoglobulin locus represent one way that human antibodies may be obtained from the immunization of mice. Newer methods are aimed at generating fully human monoclonal antibodies directly from human cells through the use of viral transformation of human primary B-cell lines or antibody-secreting plasmablasts, or by generating human B-cell hybridomas.
Monoclonal antibodies belong to a new class of therapeutic compounds called biologics, which includes other natural proteins such as anti-lymphocyte globulin, cytokines, protein fragments, and even whole cells, which are used, for example, in the adoptive transfer of T cells in cancer immunotherapy. Many monoclonal antibodies have been, or are in the process of being, approved for clinical use by the US Food and Drug Administration (Fig. 16.8), and a systematic naming process identifies the type of antibody. Murine monoclonal antibodies are designated by the suffix -omab, such as muromomab (originally called OKT3), a murine antibody against CD3. Chimeric antibodies in which the entire variable region is spliced into human constant regions have the suffix -ximab, such as basiliximab, an anti-CD25 antibody approved for the treatment of transplantation rejection. Humanized antibodies in which the murine hypervariable regions have been spliced into a human antibody have the suffix -zumab, as in alemtuzumab and natalizumab (Tysabri). The latter is directed against the α4 integrin subunit, and is used to treat multiple sclerosis and Crohn’s disease. Antibodies derived entirely from human sequences have the suffix -umab, as in adalimumab, an antibody derived from phage display that binds TNF-α; it is used to treat several autoimmune diseases.
16-6 Monoclonal antibodies can be used to prevent allograft rejection.