Mechanisms of Action of Anti-CD20 Agents
This figure depicts several ways in which monoclonal antibodies are thought to induce tumor-killing activity in B-cell malignancies.
ADCC indicates antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; FcγR, fragment crystallizable gamma receptor; IE, immunization effect; MAC, membrane attack complex; mAbs, monoclonal antibodies; NK, natural killer; PCD, programmed cell death.
In the early 1900s, German scientist Paul Ehrlich theorized that by selectively targeting disease-causing organisms, we might be able to specifically deliver a toxin to kill that organism. This “magic bullet” concept was realized to some extent for cancer therapy with the development of monoclonal antibodies.
The first anticancer antibody on the market was rituximab, which targets the membrane protein CD20 and, since its approval in the late 1990s, it has revolutionized the treatment of B-cell malignancies, with huge improvements in survival rates. However, despite its success, a large proportion of patients are rituximab-refractory
, either failing to respond or eventually relapsing. This has prompted the development of newer CD20 agents with altered structures that are designed to improve upon rituximab’s performance.
CD20’s Role in the Immune System
The T and B cells of the immune system are coated in thousands of cell-surface molecules. Among them is a group known as the cluster of differentiation (CD) proteins, which reflect the type and developmental stage of the cell to which they are attached, and which are recognized by anti-B- and T-cell antibodies.
CD20 is a member of a group of at least 26 proteins in mice and humans— the membrane-spanning 4A family. CD20 is found on the surface of all B cells at almost all stages of their development. Like many CD proteins, its precise cellular function is still unclear; however, it plays an important role in B-cell development and maturation, and is suspected of acting as a calcium channel in the cell membrane.
CD20 as Anticancer Target
The idea of using monoclonal antibodies as cancer therapy originated in the late 1970s and offered the potential for specifically killing cancer cells through antibody binding to proteins attached to the cancer cell surface. CD20 was seen as an ideal target against which to design monoclonal antibodies for a number of reasons, among them:
It is expressed by the vast majority of B-cell lymphomas.
It is not present on any other cells besides B cells, thus limiting off-target effects.
The first stage of B-cell development does not express CD20; therefore, any healthy B cells destroyed by CD20-targeted therapy can be readily replenished.
Anti-CD20 monoclonal antibody therapy has proven to be very effective, particularly when used in combination with the chemotherapeutic regimen CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine sulfate], and prednisone).
The Rituximab Revolution
In 1997, the chimeric antibody rituximab (Rituxan) became the first CD20-targeted agent to be approved by the FDA for the treatment of B-cell malignancies. It remains a staple in cancer therapy today and is approved for use as a single agent in patients with certain types of B-cell non-Hodgkin lymphoma (NHL), namely follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), and in patients with chronic lymphocytic leukemia (CLL). Approval was based on clinical trials in relapsed or refractory B-cell NHL in which an overall response rate of 48% and a median duration of response of 11.2 months were observed.
The real success story with rituximab, however, has been the synergistic activity it appears to have with several forms of chemotherapy, the mechanism of which remains uncertain. It has been possible to incorporate rituximab into these chemotherapy regimens with dramatic improvements in efficacy and without any significant additional toxicity. Response rates over 90% and median time to progression of 82 months have been observed with R-CHOP combination therapy.
Despite these remarkable responses and the substantial effects on patient survival, there are several major issues with rituximab treatment. When used as a single agent, close to half of patients fail to respond, and complete responses are seen in less than 10%. Most significantly, the majority of patients who do initially respond to rituximab treatment will eventually relapse. A number of mechanisms for the development of resistance or relapse have been proposedâŽ¯primary among them is that tumor cells can lose CD20 from their surface following treatment, resulting in CD20-negative tumor cells that are resistant to rituximab.