HAMA responses

Antibody immunogenicity remains one of the inherent therapeutic limitations associated with administration of murine monoclonals to human subjects. In most instances, a single injection of the murine monoclonal will elicit an immune response in 50-80 per cent of patients. Human anti-mouse antibodies (HAMA) will generally be detected within 14 days of antibody administration. Repeated administration of the monoclonal (usually required if the monoclonal is used for therapeutic purposes) will increase the HAMA response significantly. It will also induce an HAMA response in the majority of individuals who display no such response after the initial injection. The HAMA response will effectively and immediately destroy subsequent doses of monoclonal administered. In practice, therefore, therapeutic efficacy of murine monoclonals is limited to the first and, at most, the second dose administered. 

Humanized and chimerized MAbs have been developed for the treatment of non-Hodgkin lymphoma, renal cell carcinoma, ovarian carcinoma, breast cancer, melanoma, and neuroblastoma [117,119,120,123,124]. Patients with relapsed or refractory myeloid leukaemias that have been treated with HuM95, did not develop significant HAMA responses [59]. 

OKT-3 was first approved for general medical use in the USA in 1986. Its indication was the treatment of acute kidney transplant rejection (Table 10.4). OKT-3 is produced via ascites grown in mice. The intact antibody is subsequently purified by a combination of ammonium sulphate fractionation and anion exchange chromatography. Despite its therapeutic effectiveness, the product does display some limitations. Its antigenicity in humans (the HAMA response) is one obvious factor which limits its prolonged use. 

In addition to the immunogenic potential of murine monoclonal antibodies, another disadvantage of murine antibodies is their rapid elimination from the circulation relative to human antibodies. Muromomab has an elimation half-life of about 18 hours, whereas human antibodies have half-lives of weeks. Human antibodies have long serum persistence because they are recycled by endothelial cells. The Fc portion of murine monoclonal antibodies binds very poorly to human FcRn, and therefore murine antibodies are not recycled resulting in their poor serum persistence [7]. The converse, however, is not true. Human Fc binds well to murine FcRn, and therefore human antibodies have long serum persistence in mice. The lack of FcRn binding in combination with a HAMA response results in rapid clearance from the serum. 

The first murine monoclonal antibody was approved for marketing in 1986/ when Orthoclone (CD3-specific antibody)/ or OKT3/ was approved. NoW/ humanized antibodies/ engineered so that HAMA response is mitigated have become mainstream therapy/ with such recent successes as Raptiva/ ErbituX/ and Avastin (Table 32.1). A successful antibody also needs to be potent and specific (6). The following sections describe how engineered antibodies can be produced to meet these requirements. 

Because most monoclonal antibodies that have been studied for tissue targeting are from mouse or, occasionally, from rat, the problem of antibody production to such foreign proteins always exists. While murine-derived mAbs are well tolerated for acute therapy, their use in chronic therapy is limited, due to severe human anti-mouse antibody response (HAMA) [231]. The HAMA response is elicited due to the foreign nature of the antibody itself. Molecular engineering is being utilized to replace the foreign components of the murine antibody with human antibody sequences to overcome their immunogenicity [232]. 

J. J. Tjandra, L. Ramadi, and I. F. McKenzie, Development of human anti-mirrine antibody (HAMA) response in patients. Immunol Cell Biol 68(Pt 6) 367-376 (1990). 

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