Rituximab

Structure

Rituximab is a 145-kDa chimeric murine-human monoclonal IgG ₁ κAb directed against the CD20 antigen expressed on B cells ( Table 30.1 ). The chimeric Ab is comprised of two mouse variable regions that recognize CD20, two human IgG ₁ heavy chains, and two human κ light chains ( Fig. 30.1 ). It is manufactured in Chinese hamster ovary (CHO) cells through the use of recombinant DNA technology.

Pharmacokinetics

Q30.2 As a targeted monoclonal Ab, the pharmacokinetics of rituximab are largely influenced by the characteristics of the Ab isotype, as well as the amount and location of its target, CD20. Human IgG ₁ antibodies have a half-life of about 21 days in the circulation, and this is within the range of what has been measured for rituximab. Clearance is thought to be primarily through phagocytosis.

A pharmacokinetic analysis of 2005 RA patients, receiving rituximab, determined an estimated clearance of 0.335 L/day, and the volume of distribution was 3.1 L. Q30.2 The mean terminal elimination half-life was 18 days. Because of patient to patient variation in the amount of CD20, especially in the setting of B cell malignancy, the half-life of rituximab can vary dramatically among individuals. In addition, levels of serum rituximab increase with repeated doses, as B cell depletion leads to less and less available CD20 antigen.

Q30.3 Rituximab therapy typically leads to depletion of peripheral blood B cells 2 to 3 weeks after treatment initiation. Depletion of peripheral blood B cells is sustained for 6 months on average, and peripheral blood B cell numbers usually return to normal levels within the first year after treatment. Plasma cells are not depleted and serum Ig levels do not decline markedly.

Age, weight, and gender do not appear to affect rituximab pharmacokinetics. Studies have not evaluated pediatric or adolescent populations or adults with hepatic or renal impairment, but dosing adjustments are not generally recommended.

Mechanism of Action

Q30.4 Rituximab is a chimeric monoclonal Ab that binds to CD20 on the surface of CD20+ B cells and induces their depletion. CD20 is a cell-surface antigen expressed nearly exclusively on B cells, beginning at the pre-B cell stage of development, and continuing on to mature, activated and memory B cells. Hematopoietic stem cells, pro-B cells, short-lived plasmablasts and long-lived plasma cells do not express CD20, and thus are not directly affected by rituximab. Short-lived plasmablasts are indirectly depleted, as their CD20+ progenitors are targeted ( Fig. 30.2 ).

Q30.4 Rituximab depletes B cells through three known mechanisms ( Fig. 30.3 ):

• (1)

  Ab-dependent cellular cytotoxicity. Immune effector cells expressing Fcγ receptors, particularly natural killer cells, bind CD20+ cells coated with the IgG ₁ isotype rituximab Ab. Upon receptor binding, effector cells secrete cytotoxic granules and kill CD20+ B cell via cytolysis.

• (2)

  Complement-mediated cytolysis. Binding of rituximab to CD20 allows for the activation of the classical complement pathway, resulting in insertion of the membrane attack complex into the plasma membrane and the induction cell death.

• (3)

  Signaling induced cell death. Rituximab binding can also induce CD20 signaling and promote cell death. Although incompletely understood, such signaling may involve alterations in p38 mitogen-activated protein kinase (MAPK), nuclear factor(NF)-κB, extracellular signal regulated kinase (ERK) 1/2 and protein kinase B (AKT) pathways.

Q30.5 Effect of rituximab on pre-existing immunity. Much of acquired immunity to infectious disease, induced by immunization or natural infection, is maintained by standing Ab titers generated by long-lived plasma cells. Plasma cells are CD20– and are not directly targeted by rituximab. Thus, rituximab spares much of the immunity a recipient has acquired over his or her lifetime. Indeed, multiple studies have shown that after rituximab treatment, individuals retain grossly normal serum titers of Ab to pneumococcus, tetanus toxoid, and varicella zoster virus.

Q30.6 Effect of rituximab on the formation of new immunity. New B cells are continually generated in the bone marrow and enter into the blood, lymphatics, spleen and peripheral tissues to surveil for infectious agents. Although rituximab depletes the bulk of the B cell pool, CD20 ⁻ hematopoietic cells, common lymphoid precursors and pro-B cells are spared. Thus, after rituximab treatment is completed and the drug itself is catabolized, the B cell compartment regenerates. New immune responses to vaccines and infections are impaired for a time but are eventually restored. As early as 4 months postrituximab, autoimmune blistering disorder patients have been observed to mount grossly normal responses to influenza vaccination. Although the investigators favor that the influenza response are mounted by memory B cells, not depleted by rituximab, rather than newly generated naïve B cells, this observation highlights the potential of the B cell response to recover postrituximab.

Q30.5 Effect of rituximab on pathogenic autoimmunity. In pemphigus, rituximab depletes pathogenic antidesmoglein-specific CD20+ B cells. The high serum and tissue titers of antidesmoglein antibodies characteristic of active pemphigus are produced by short-lived plasmablasts. These pathogenic plasmablasts are indirectly depleted when rituximab depletes their direct CD20+ B cell precursors. Before the clinical use of rituximab for pemphigus, it was unknown if long-lived plasma cells or short-lived plasmablasts were responsible for generating disease-inducing Ab. When clinical improvement and reduction in antidesmoglein Ab titers were observed in the first months after rituximab, it became clear that short-lived plasmablasts were the primary drivers of disease.

Q30.7 In addition to the decline of circulating autoreactive B cells and their corresponding Ab, B cell depletion by rituximab leads to secondary effects on the immune system. Studies have noted decreased costimulatory molecules on CD4+ T cells, decreased numbers of memory T cells and increased numbers of regulatory T cells. In pemphigus, rituximab therapy results in a decrease in desmoglein reactive CD4+ T cells. In patients who achieve complete remission postrituximab, an expanded interleukin (IL)-10-producing B regulatory cell compartment has been observed. Together these observations indicate that rituximab therapy indirectly triggers immunomodulatory effects beyond the direct depletion of pathogenic B cells.

Durability of the antiautoimmune response. In pemphigus, most patients treated with a single cycle of rituximab achieve remission but subsequently relapse, although a minority achieve durable remission off all therapy. Q30.8 Experimental data suggest that recurrent disease is mediated by residual clones, identical in specificity to those present at disease onset. Further, pathogenic clones are few in number and new clones are rarely observed over the disease course. These data suggest that success of rituximab therapy hinges on effective elimination of a small group of CD20+ antidesmoglein B cell clones. These findings complement and extend clinical observations described earlier and suggest that rituximab initiation, early in disease course and with higher and repeated dosing, may result in a more favorable and durable response.

US Food and Drug Administration-Approved Indications

Q30.7 Rituximab is FDA approved for the treatment of NHL, CLL, refractory RA, GPA, MPA and moderate to severe PV (see Box 30.1 ).

Off-Label Dermatologic Indications

Rituximab has been used off-label for several dermatologic conditions, in which B cells play a role in disease pathogenesis (see Box 30.1 ). Experience for these indications is summarized subsequently.