Therapeutic Challenges

Between 1975 and the early 1990s, researchers in MoAb therapy suffered a variety of setbacks and challenges. Patients treated with the agents in clinical settings did not show dramatic responses. The initial murine products were hindered by the development of HAMA (human anti-mouse antibodies); host antibodies identified murine protein fragments as foreign, subsequently inactivating the compounds after repeated administra-tion.1 This was further complicated by allergic-type reactions and even anaphylaxis. Other potential reasons for the limited success of these compounds included short drug half-lives, inadequate recruitment of the patients' immune effector cells, lack of specificity of tumor antigens, internalization of the target antigen by tumor cells, and inadequate quantities of antibody administered.1 With the advancement of technology and laboratory techniques involved in the production of antibodies, as well as clinical research in genomics and cellular-signaling pathways, the development of therapeutic MoAbs has improved significantly in the past 15 years. Production of humanized and human chimeric antibodies, as well as clinical advances in identification of antigenic receptors, has resulted in the FDA approval of 17 MoAbs since 1986. Eight of these compounds received approval for cancer indications (Table 103.1).

APPROVED COMPOUNDS Rituximab (Rituxan)

Rituximab, the most extensively studied MoAb to date, is a chimeric human/mouse IgG1-K MoAb designed to target cell surface protein CD20. Rituximab consists of murine variable regions from the parent 2B8 MoAb grafted onto a human IgG1 constant-region backbone.5 The cell surface protein CD20 offers an ideal target, as it is expressed on >95% normal B lymphocytes and B-cell lymphomas, but not stem cells or plasma cells. Additionally, CD20 is not shed or internalized upon antibody binding; thus, the antibody-CD20 complex remains on the surface of the cell, available to bind and stimulate ADCC and CMC.8 In addition to ADCC and CMC, rituximab achieves therapeutic activity by direct induction of calcium influx

Table 103.1 Monoclonal antibodies currently approved for the treatment of hematologic and oncologic malignancies7

Monoclonal antibody

Target antigen

Clinical uses

0 0

Post a comment