BIOLOGIC AGENTS AND IMMUNOTHERAPY IN RHEUMATOID ARTHRITIS: Progress and Perspective

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Advances in our understanding of rheumatoid synovitis have been coupled with increasingly refined methods from biotechnology to produce promising therapeutic agents. Monoclonal antibodies (MoAbs), recombinant cytokines, cytokine receptor fusion proteins, and other biologics have moved from the status of novel reagents applied in phase I toxicity trials to, in some cases, substantially evaluated and validated tools awaiting federal regulatory approval. Biologic agents will soon be released for the treatment of patients with rheumatoid arthritis (RA).

This article will be directed toward clinicians who manage patients with RA and investigators engaged in studies of RA therapeutic interventions. Attention will be directed toward selected preclinical studies as well as trials already completed in human subjects. We will focus on findings that appear promising for further investigation or where important lessons have been learned. We will review strategies for RA intervention and make recommendations regarding the design and evaluation of future therapeutic trials. We will also speculate on the potential role for biologics in future management of patients with RA.

The various cells and molecules engaged in rheumatoid synovitis are well known to students of this disease.33, 80, 83 Each can be considered a potential target for therapeutic intervention.59, 127 Biologic agents known to be under consideration in RA therapeutic trials are outlined in Table 1. These RA trials reflect in part the historical availability of MoAbs, recombinant cytokines, and other biotechnology-derived agents as well as an emerging sophistication in our understanding of the apparently critical targets [e.g., TNFα, T-cell receptor (TCR)] or “leverage points” in the disease process. In addition, the biologic products developed thus far reflect an evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents which maximize the efficacy/toxicity relationship (therapeutic index).

Therapeutic strategies for RA intervention are shown in the list that follows.

  • 1

    Inhibition of cellular function

  • Nondepleting anti-T-cell MoAb

  • Anti-activation/costimulation/adhesion MoAb

  • Recombinant anti-inflammatory cytokine

  • 2

    Inhibition of cytokine/receptor function

  • Blocking MoAb to proinflammatory cytokine or receptor

  • Inhibition of cytokine synthesis or expression

  • Cytokine receptor administration

  • Cytokine receptor fusion protein

  • Competing peptide receptor antagonist

  • Inhibition of cytokine-induced intracellular signaling

  • 3

    Immune deviation (TH1 to TH2 phenotype)

  • Recombinant anti-inflammatory cytokine

  • 5

    Tolerance induction

  • Antigen (Ag) administration, mucosal (oral, intranasal) or parenteral

  • Recombinant anti-inflammatory cytokine

This list categorizes the approaches utilized in prior studies and provides a conceptual framework for consideration of future studies. It is our belief that greater clarity regarding important therapeutic targets and improved products in the research and development pipeline justify optimism regarding future therapy of RA.

Section snippets

T-CELL DEPLETION AND INHIBITION

The rationale for evaluating T-cell directed therapies in RA has been extensively discussed previously.11, 71 Although some observers have promoted a T-cell independent model of rheumatoid synovitis, several lines of evidence support the importance of the T cell in RA: (1) CD4 T cells predominate in the early synovial lesion; (2) a purely T-cell mediated arthritis can be induced in animal models and transferred via T lymphocytes to immunologically naive animals; (3) some RA patients improve in

CYTOKINE-BASED THERAPIES

Many cytokines have closely related or overlapping effects, and induce multiple biologic responses. They can be grouped into families based on shared amino acid sequences and cells of origin. Some of these families include the hematopoietic growth factors, interferons, Ig superfamily members, and chemokines. Receptors for cytokines can also be grouped into families based on their shared association with specific signal transducing protein kinases, which may explain some overlap in cytokine

TNFa INHIBITION

The last decade has witnessed the emergence of TNFα as a critical molecule in rheumatoid synovitis. High serum levels of TNFα (cachexin) had previously been observed in patients with anorexia and weight loss from severe RA. TNFα was subsequently found at significant levels in rheumatoid synovial fluid94 and widely expressed in rheumatoid synovial tissues.22 It was also found at significant levels in supernatants from rheumatoid synovial cells in culture. TNFα induced expression of

TOLERANCE INDUCTION

Clones of T cells bearing high affinity TCRs for self-antigens (autoreactive T cells), for the most part, are deleted via apoptosis in the thymus after interaction with thymically-expressed autoantigens. Since this mechanism for deleting autoreactive T cells is not complete, remaining T cells that recognize self-antigens are controlled by at least two peripheral mechanisms of tolerance: (1) T-cell interaction with antigen occurring in the absence of necessary activation or costimulation signals

ANTI-ADHESION THERAPY

Adhesion molecules expressed on tissue cells and circulating leukocytes are thought to play a pivotal role in lymphocyte homing to lymphoid tissues, migration of leukocytes to inflammatory sites, and costimulation in cellular activation. Nearly three dozen cell surface molecules that can function as adhesion proteins have been identified and the potential role of adhesion molecules in rheumatic disorders has recently been reviewed.66 Extravasation of leukocytes is thought to occur in four

TRIMOLECULAR COMPLEX (TMC) INHIBITION

The TMC (TCR/antigen/MHC) confers specificity to immunologic reactions and is probably the most selective and proximal target for immunotherapeutics. In this context, RA is considered an antigen- or superantigen-driven process (where the antigen remains unknown) that stimulates antigen processing by APCs and interaction with T cells bearing the highest affinity TCRs, with subsequent restricted clonal activation and expansion of T cells that ignite the inflammatory cascade and fail in some way

THERAPIES DIRECTED TOWARD GROWTH CONTROL/APOPTOSIS

Increasing attention has recently been directed toward a “malignancy” model of rheumatoid synovitis, in which invasive synovial cells (particularly the synovial fibroblast-like cells found in pannus invading articular bone and cartilage) may be “transformed” by expression of oncogene products.34, 127 Synovial cells in culture and in tissue sections express a number of proto-oncogenes, which are markers of cellular activation and anchorage independence. Programmed cell death, or apoptosis, is

LESSONS FROM THE PAST AND FUTURE DIRECTIONS

What have we learned after a decade of therapeutic trials with biologic agents in patients with RA? Biologics must deliver on the promise of improved efficacy while meeting the same high standards for safety observed with current pharmaceuticals. The experience with anti-T-cell MoAbs underscores the central importance of prospective, randomized, and controlled studies (often requiring placebos) in establishing therapeutic efficacy. In addition, careful dose-escalation and dose-finding studies

ACKNOWLEDGMENTS

We would like to thank Debbie Granner for her help in the typing of the manuscript for this article.

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