B-Cell Targeted Therapy in Autoimmunity

Written by: Judy Seraphine Based Upon a Presentation Delivered by Arthur Kavanaugh, MD at the 2012 Maui Derm 

Introduction

B cells may play a prominent role in a number of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, pemphigus/pemphigoid, vasculitis, and many others. The mechanisms by which B cells may play a role in autoimmunity include autoantibody secretion, modulation of immune/inflammatory reactions via ctyokines and other mediators, antigen presentation / co-stimulation of T cells, and  lymphoid organogenesis in target organs. The activity of B cells in autoimmunity represents a loss of immunologic tolerance. The targeting of B cells specifically is now possible; the first approved agent being the anti-CD20 monoclonal antibody, rituximab. Clinicians should be aware that B cells may be targeted in many other ways and the results on the efficacy and safety of these approaches are forthcoming. Safety issues related to targeting of B cells may be both agent-specific as well as target-specific and the major concerns include the potentially increased risk of infections.

B Cells – Autoimmunity: History

Paul Ehrlich, the “Grandfather” of autoimmunity, first studied B cells in autoimmunity via histologic staining and the identification of blood cells. More importantly, Dr Ehrlich came up with the side chain theory, i.e., a specific receptor for a counter-receptor on a type of cell. This really helped develop chemotherapy or the “magic bullet” theory, i.e., a single, very focused therapy would go straight to its target and not hurt the other tissue. However, scientists noted that this could go wrong and; therefore started what was known as “horror autotoxicus”, the idea that the body was attacking itself. In Rheumatology, the identification of autoantibodies, specifically rheumatoid factor (RF) and anti-nuclear antibodies (ANA) came about in the 1940s and really brought B cells into the forefront.  In 1952, Bruton researched  X-linked agammaglobulinemia, and the 1960s researchers began to the identify B cells. In the 1960s and 1970s, there was very important work done in autoimmunity, specifically, clonal deletion, clonal anergy and idiotypic network.  In 1975, monoclonal antibodies were developed which really paved the way for modern immunology. In 1997, rituximab was approved for NHL. In 2006, rituximab received approval for RA and in 2011 it was approved for WG/MPA.

B cells are the source of all immunoglobulins and can be activated by antigen in conjunction with co-stimulatory signals provided by antigen-presenting cells (APCs) and T lymphocytes. If successfully stimulated, activated B cells differentiate into antibody-secreting plasma cells. Most plasma cells generated during the initial phase of clonal expansion are short-lived and tend to produce IgM antibody.

In the second phase of clonal expansion, high-affinity (germinal center) B cells give rise to long-lived plasma cells and extremely long-lived memory B cells. When memory B cells re-encounter antigen, they rapidly differentiate into plasma cells and proliferate into more memory B cells. The plasma cells themselves are “terminally differentiated” and are no longer able to divide in response to antigen.

Reference:
Ahmed R, Lanier JG, Pamer E. Immunological Memory and Infection. In: Kaufman SH, Sher A, Ahmed R, eds. Immunology of Infectious Diseases. ASM Press; 2002:175–189.

What do B Cells do in Autoimmune Disease?
  1. Production of autoantibodies
  2. Co-stimulation/antigen presentation
  3. Immunomodulation/cytokine secretion
  4. Lymphoid organogenesis

In rheumatoid arthritis, the efficacy and safety of rituximab has been demonstrated in several studies. With the use of rituximab also comes B cell depletion; however, only about 60% of patients respond; therefore, there is no correlation with clinical response. So what is the mechanism of depleting B cells? Is it bone marrow B cells? Is it synovial B cells? Scientists are still not sure what the specific target is.  We’re not always sure why they work. A related issue in rheumatoid arthritis is a biomarker and the idea of personalized medicine. The patients who were positive for RF or ANA, tended to do better with rituximab.  

Many open studies showed that perhaps B cell therapy would work in SLE.

Why did the EXPLORER study fail?

There was no statistical significance between rituximab and placebo and there were no differences by AUC of total activity, landmark analyses, or flares in “responders”.

The study demonstrated that rituximab significantly depleted CD19+ B cells and there were significant reductions in adsDNA, ACL Abs; memory CD8+ T cells. In summary, high dose steroids with prolonged taper may have blunted the effects of rituximab, and longer term follow-up may have shown beneficial effect but open-label extension was cancelled due to PML concerns. Healthcare providers should also be aware that BILAG is a difficult instrument to use and/or adjudicate.

There is another line of thought that is dedicated to the differential effects of rituximab on serum autoantibody levels, i.e., some diseases are rituximab-sensitive; some are partially rituximab-sensitive and some are rituximab-resistant.

We are now thinking of our targets based on the types of B cells that we may be eliminating or modulating with different types of therapies.

Targeting B Cells
  • Anti-CD20:
    • Rituximab
    • Ofatumumab (HuMax CD20):
    • Ocrelizumab
    • Trubion synthetic anti CD20
    • B-cell growth factors
      • BR3-Fc
      • Atacicept [TACI-Ig
      • Belimumab (anti-sBLyS)
      • Anti-CD22
        • Epratuzumab
        • Anti-CD40L (CD154)
          • Studies halted
BLyS/BAFF: Ensuring B Cell Survival

BLyS/BAGG is potentially expressed by multiple immune cells, specifically neutrophils, monocytes, B cells, activated T cells, plasma cell, and dendritic cells. It exists in membrane-bound and soluble forms. Three molecules bind together to form the trimeric soluble protein; soluble BLyS is considered to be the active form. BLyS is important in ensuring that new B cells mature, survive, and differentiate themselves. BlyS (BAFF) levels are elevated in patients with SLE.

Belimumab

Belimumab received FDA approval in May of 2011. The only prior FDA approved drugs for SLE were aspirin, prednisone, and HCQ. Belimumab is considered to be relatively safe, but its efficacy is modest (cutaneous outcomes; only significant for rash, not alopecia, oral ulcers: improved BILAG rash seen in placebo – 30% / 1 mg – 42% / 10mg – 44%). There is a question as to its utility as a steroid-sparing agent in milder lupus. The long-term efficacy, safety and cost of belimumab are yet to be determined.

Epratuzumab, the anti-CD22 mAb, is currently under study in SLE.
Anti-neutrophil cytoplasmic antibody (ANCA) Associated Vasculitis (AAV)

What about using B cell therapy in the ANCA-associated vasculitides? In the RAVE study (RTX vs CTX), rituximab demonstrated increased efficacy (63.6% v 51.1%).  Looking at long-term efficacy, a single course of rituximab is as effective as 18 months of standard therapy with cyclophosphamide and azathioprine.

Clinicians should also note that rituximab has also had a dramatic effect in patients with MS.

Safety Issues with B Cell Targeted Therapies

There are a number of safety issues with the use of biologic DMARDs in RA, including serious infections, opportunistic infections such as tuberculosis (TB), malignancies, demyelination, hematologic abnormalities, administration reactions, congestive heart failure, and autoantibodies and lupus.

Target Related

•Impaired humoral immunity / B cell costimulatory function

•Infections / serious infections

•Impaired vaccine responses

Agent Related

•Infusion / administration reactions:

•RTX: mostly on 1st infusion; mild (common) à severe (rare)

•RTX: lesser frequency / severity, RA vs NHL

•Immunogenicity: antibodies to treating agent

•RTX: HACA ~ 1% NHL studies; ~ 4%-12% RA studies

•? Clinical relevance ?

Conclusions

There is a lot of promise with targeting B cells. There are lots of potential mechanisms that may have varying efficacy and different safety concerns. There is a lot of excitement in the future for B cell directed autoimmune diseases.