The anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell malignancies. This unprecedented success has not only substantially changed the mindset of the clinical community about the ability of mAb to improve outcomes but has catalyzed the interest in the pharmaceutical industry to develop the next generation of anti-CD20 mAbs. Since the introduction of rituximab 15 years ago, we have learned much about the potential mechanisms underlying the therapeutic efficacy of anti-CD20 mAbs. In parallel, many novel anti-CD20 mAbs have entered the clinic, each designed with modifications to structure aimed at further improving efficacy. On review of the newer generation of anti-CD20 mAbs entering clinical trials, it appears that the link between the novel mechanistic insights and the development of these next-generation anti-CD20 mAbs is unclear. As we move into an era of personalized medicine, it will become increasingly important for us to develop closer links between the emerging mechanistic insights and the clinical development, to further enhance the potency of anti-CD20 mAbs beyond that achieved with rituximab. (Blood. 2011;117(11): 2993-3001)
IntroductionThe advent of monoclonal antibody (mAb) technology after the Nobel Prize-winning scientific contribution of Kohler and Milstein 1 led to a great expectation that mAbs would provide effective targeted therapy for cancer. After early promise came a period of despondency in the late 1980s and early 1990s with largely disappointing early phase clinical trial results, with the notable exception of anti-idiotype antibodies in follicular lymphoma (FL). 2,3 More than 20 years elapsed before mAbs began to fulfill their early promise as effective anticancer therapeutics, and many lessons were learned from these clinical trial failures. When the first successes were seen in hematologic malignances, the importance of the antigen target specificity and developing "humanized" mAbs was recognized. In hematologic malignancies, the major success of mAb therapy to date has been seen with anti-CD20 mAbs. Although the first B cell-specific antibody B1 (renamed tositumomab), which targets the B cell-specific antigen that we now know as CD20, was discovered as long ago as 1981, 4 it was not until 1997 that the anti-CD20 rituximab became the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for use in relapsed indolent lymphoma. 5 mAbs are now routinely delivered in a wide range of hematologic malignancies, and rituximab is widely accepted to be the single most important factor leading to improved outcome in a range of B-cell lymphomas 6-10 and more recently in B-cell chronic lymphocytic leukemia (B-CLL). 11,12 As we reflect on the development of rituximab in the late 1990s, there were considerable challenges and uncertainties for those early pioneers to overcome in integrating rituximab into treatment protocols. Given those difficulties, much of what has now become standard practice was the result of serendipity and pragmatism ...