Antibody guided precision radiation therapy

Extract: Hybridoma/monoclonal antibody (mAb) technology as described in Kohler and Milstein's work resurrected Ehrlich's century old concept of "magic bullets." This seminal publication described fusion of a plasmacytoma (tumor of activated B lymphocytes) with spleen cells and subsequent isolation of hybrids that secreted mAb with pre-defined specificity. Generation of mouse mAbs against tumor-associated antigens became a focus in the 1980's. Pre-clinical studies provided proof-of-concept for the potential of mAbs for therapy although inherent limitations of these models demonstrated discordance in predictability of actual efficacy. Clinical investigations also illustrated deficiencies; foremost, an inevitable immune response, i.e., the production of human anti-murine immunoglobulin antibodies (HAMA). Other limitations included (1) inadequate tumor dose delivery; (2) insufficient activation of effector function(s); (3) slow blood clearance; (4) low affinity and avidity; (5) normal organ targeting; (6) tumor antigen heterogeneity; and (7) insufficient tumor penetration. Most of these were handled with genetic engineering or chemical modification, but some obstacles remained. HAMA production has been addressed by chimerization (combining portions of mouse and human antibodies) or complete humanization (grafting only the key antigen-binding portions of mouse antibody to a human antibody framework) of the mAb.