Emerging therapies in rheumatoid arthritis: focus on monoclonal antibodies

Introduction

In recent years, dramatic advances have emerged across medical disciplines in understanding the pathogenesis of immune-mediated inflammatory diseases, which are accompanied by a significant shift in treatment options¹. One of the most significant advances has been shown in the treatment of rheumatoid arthritis (RA), in which the discovery of glucocorticoid activity was among the first therapeutic milestones in the 1950s², followed by widespread use of methotrexate since the turn of the 1980s and 1990s³. Later on, success in the treatment of RA can be attributed to the introduction of new classification criteria allowing earlier diagnosis and treatment and application of the treat-to-target principles with the aim to induce remission or at least low disease activity^4–6. The biggest breakthrough in the treatment of RA, however, comes with biologic therapy, which has gradually begun to spread since the beginning of the new millennium with the introduction of tumor necrosis factor (TNF) inhibitors into clinical practice⁷.

Targeted disease-modifying antirheumatic drugs (DMARDs), consisting of biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), antagonize soluble cytokines and their receptors and directly affect immune cell activity or intracellular signaling pathways^8–10. The effect of targeted therapies is relatively rapid and often accompanied by a significant suppression of inflammation. In most cases, it can substantially improve quality of life and stop or significantly slow the progression of functional and structural impairment¹¹. Currently, out of the biological therapies, five original TNF inhibitors and already even more biosimilar TNF inhibitors, two interleukin-6 receptor (IL-6R) inhibitors, and one IL-1 receptor inhibitor as well as B-lymphocyte (CD20) and co-stimulatory signal (CD28-B7 interaction) for T-cell activation inhibitors are available for the treatment of RA (Table 1). In addition to bDMARDs, two tsDMARDs, including Janus kinase inhibitors (JAKi) tofacitinib (pan-JAKi) and baricitinib (JAK1/2i) (Table 1), have expanded the treatment armamentarium¹².

Although the fate of patients with RA has improved significantly and a milder course of disease can be observed than in the past¹³, persistent remission, let alone drug-free remission or complete cure, is still elusive¹⁴. This review will outline several new directions for the potential new therapeutic antibodies and treatment strategies for RA, new biological drugs against new targets, and biological drugs against already-known targets that are currently in early or late stages of clinical development.

Cytokine and cell-targeted therapies

The development of biological therapies for RA has been facilitated by two main assumptions. The first prerequisite is an increasing understanding of the pathophysiological processes in which systemic immune mediators, immune cells, and signaling pathways play a role and have become targets for specific immune interventions¹⁵. The second important assumption is the dynamic development of the pharmaceutical industry and advances in genetic engineering and biotechnology¹⁶. Potential therapeutic antibodies that are in various stages of clinical development are summarized in Figure 1.

Figure 1. Potential biological therapies for the management of rheumatoid arthritis that are currently in various stages of clinical development.

Black text shows therapies that were effective in the treatment of rheumatoid arthritis, although some of the drugs are not further evaluated in rheumatoid arthritis owing to company prioritization. White text shows therapies that failed to prove efficacy or whose clinical trials were terminated owing to safety concerns.

*However, anti-CD20 monoclonal antibody such as rituximab is effective and licensed for the treatment of rheumatoid arthritis.

BAFF, B-cell activating factor; CXCL, C-X-C motif ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; IL, interleukin; mAb, monoclonal antibody; TNF, tumor necrosis factor; Treg, T regulatory

New targets in later phases of development

Old targets with the focus on interleukin-6

In mid-2017, sarilumab (trade name Kevzara), a human monoclonal antibody against IL-6R, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA. Sarilumab showed significantly greater affinity to recombinant human IL-6R compared with tocilizumab and longer half-life with a similar safety profile^28,29. Further biological drugs targeting IL-6 pathways are in development.

Clazakizumab (formerly ALD518 and BMS-945429) is a humanized monoclonal antibody against IL-6. In a phase IIb study³⁰, the primary endpoint was met; ACR20 response rates at week 12 were greater for clazakizumab (25, 100, and 200 mg) once monthly in combination with methotrexate (MTX) or clazakizumab monotherapy (100 and 200 mg) versus MTX (76.3%, 73.3% and 60.0% or 55.0% and 61.0% versus 39.3%; p<0.05). Also, remission rates as assessed by DAS28-CRP for clazakizumab plus MTX were greater than for MTX plus original adalimumab (40.0–49.2% versus 23.7%). The treatment was well tolerated with no unanticipated safety signals, consistent with the known pharmacologic effects of IL-6 blockade. Bristol-Myers Squibb has decided, based on portfolio prioritization, to return worldwide rights to clazakizumab to Alder BioPharmaceuticals. However, no further trials in RA are ongoing. The drug is currently in the early phases of development for the treatment of kidney transplant recipients with late antibody-mediated rejection (ClinicalTrials.gov Identifier: NCT03380377 and NCT03380962).

Olokizumab (CDP6038), a humanized monoclonal antibody against IL-6, was formerly developed by UCB Pharma and out-licensed to R-Pharm in 2013. In a phase IIb study, the primary endpoint was met; patients with active RA who had previously failed TNF inhibitor therapy demonstrated a significant decrease in DAS28-CRP at week 12 for all doses (60 mg, 120 mg, and 240 mg) administrated every four or every two weeks with results comparable to tocilizumab³¹. Safety data were consistent with the use of IL-6-targeted therapy. Although no further results have been reported, phase III studies (CREDO) are either completed (ClinicalTrials.gov Identifier: NCT02760368, NCT02760433) or ongoing (ClinicalTrials.gov Identifier: NCT02760407, NCT03120949).

Sirukumab (CNTO-136; proposed trade name Plivensia), a human monoclonal antibody against IL-6, was developed by Centocor, GlaxoSmithKline, and Janssen Biotech. Sirukumab was investigated at doses of 100 mg and 50 mg every two and four weeks, respectively, in five phase III trials (SIRROUND) in a broad spectrum of patients with RA³². Sirukumab showed significant improvements in disease activity, physical function, and quality of life along with inhibition of radiographic progression^33,34. In a head-to-head study with adalimumab, sirukumab monotherapy showed greater improvements in disease activity (DAS28) but similar ACR50 response rates at week 24³⁵. Although the long-term safety of sirukumab seems to be similar to that of other IL-6-inhibiting agents, drug regulatory authorities suggested re-evaluating the safety profile of sirukumab for increased mortality rates in post open-label studies³². Interestingly, the drug is currently under development for the treatment of major depressive disorder (ClinicalTrials.gov Identifier: NCT02473289).

New targets in early phases of development

Unsuccessful biological therapies in rheumatoid arthritis

Although several pro-inflammatory cytokines play a significant role in the pathogenesis of RA and their inhibition contributed to a significant reduction in synovial inflammation and joint damage in an experimental model of arthritis and proved to be effective in early phases of development in humans, further studies failed to confirm significant efficacy⁴⁶ (Table 2). For instance, IL-1 inhibitors are approved but only modestly effective in RA while highly effective in several autoinflammatory diseases⁴⁷. An early phase study with IL-15 inhibitor therapy seemed to be efficient⁴⁸, but a phase II clinical trial of a fully human monoclonal antibody against IL-15 failed to confirm significant efficacy (ClinicalTrials.gov Identifier: NCT00433875). Although targeting the IL-23/17 axis is effective in spondyloarthritis⁴⁹, strategies to block the IL-17 pathway, IL-12/23 p40, or IL-23 did not prove to be effective in patients with established RA, and the clinical research programs in RA were discontinued⁵⁰. Similarly, the IL-20 family of cytokines such as IL-20 and IL-22 play a significant role in the process of immune cell activation and bone destruction, and although an early phase trial with the IL-20 inhibitor fletikumab was well tolerated and effective, particularly in patients with seropositive RA, further studies with fletikumab and also IL-22 inhibitor fezakinumab were completed several years ago with negative or no final results released^51,52. Although IL-21 plays an important role in the activation of the immune system, an early phase first-in-man trial with an IL-21 inhibitor (NNC0114-0000-0005) in patients with RA and healthy subjects was finished in 2012 and no further results have been released (ClinicalTrials.gov Identifier: NCT01208506). The first study demonstrating good safety and clinical efficacy of a chemokine inhibitor in patients with RA evaluated eldelumab (MDX-1100), a fully human anti-CXCL10 (anti-IP-10) monoclonal antibody⁵³; however, no further data were released.

Several strategies to inhibit B-cells were tested; for instance, humanized and human monoclonal antibodies ocrelizumab (trade name Ocrevus) and ofatumumab (trade name Arzerra) proved to be effective in patients with RA. However, after risk/benefit consideration, further studies were discontinued⁵⁴. In order to reduce the molecule, promote penetration to sites of inflammation, and improve efficacy, single-chain antibody polypeptides known as SMIPs (small modular immunopharmaceuticals) have been developed that are approximately one-half to one-third of the size of the standard monoclonal antibody. A next-generation, humanized SMIP protein therapeutic against the CD20 antigen (SBI-087) was evaluated in patients with RA, but further development was terminated⁵⁵. In addition, a further strategy to inhibit B-cell differentiation and survival via anti-B-cell activating factor (anti-BAFF) antibody has also failed in the treatment of patients with RA⁵⁶. Direct T-cell-targeting therapies such as alemtuzumab, keliximab, and clenoliximab did not show satisfactory results and were accompanied by a number of serious adverse reactions associated with severe CD4⁺ T-lymphopenia and rash⁵⁷. Tregalizumab (BT-061) is a humanized agonist antibody that selectively activates Treg lymphocytes and was tested as an innovative treatment for RA; however, it also did not show significant clinical benefit⁵⁸.

Recently, a novel approach targeting synovial fibroblasts in RA via the inhibition of cadherin-11 was presented⁵⁹. Although an interesting concept, anti-cadherin-11 (RG6125) given on top of anti-TNF therapy in patients with active RA failed to be more effective than placebo and the study was discontinued⁵⁹.

Next-generation antibodies

Conventional monoclonal antibodies (e.g. infliximab or adalimumab), Fc fusion proteins (etanercept and abatacept), and one antibody-derived molecule, a PEGylated anti-TNF Fab fragment (certolizumab pegol), are widely used for the treatment of patients with RA. Further advances in antibody engineering have led to the development of so-called next-generation therapeutic antibodies representing antibody fragments, dual/bispecific targeting variants, and immunocytokines^60–62. The purpose is to develop antibodies that are smaller, more stable, have higher affinity and improved tissue penetration, and have lower immunogenicity and toxicity than conventional antibodies. For instance, nanobodies are single-domain antibodies that were originally developed after the discovery of camelid antibodies consisting of heavy chain variable domain (lacking the Fc-equivalent region) and can be engineered to bind to two (or even more) different antigens or epitopes on the cell surface, so-called bispecific (even multispecific) antibodies^61,62. These antibodies are frequently used to treat cancer. Another therapeutic success was achieved by the development of immunocytokines, a fusion of an antibody and cytokine, which are widely studied as an anticancer therapy⁶³ and should extend cytokine half-life, reduce systemic adverse events, and deliver the cytokine specifically to sites of inflammation as mentioned above (Dekavil or AMG 592).

Belgian biopharmaceutical company Ablynx has developed unique new-generation bispecific therapeutic nanobodies ozoralizumab (ATN-103) and vobarilizumab (ALX0061) for the treatment of RA, the first humanized bispecific nanobodies, which neutralize TNF and IL-6R, respectively, and also bind to human serum albumin to increase the half-life. Ozoralizumab was tested in subcutaneous form at a once-monthly dosing interval in patients with RA and after 12 weeks of treatment, EULAR response was obtained in 97% of patients, an ACR20 response was achieved in 84%, and DAS28 remission was seen in 38% of patients with RA⁶⁴. A phase II study evaluating long-term safety and tolerability was completed in 2012 (ClinicalTrials.gov identifier: NCT01063803), and no further reports of development have been made so far. An early phase study with vobarilizumab demonstrated promising results as well, with ACR20 response rates of up to 84% and DAS28 remission rates of up to 58%⁶⁵. In addition, in a phase IIb monotherapy study (head-to-head versus tocilizumab) in RA patients⁶⁶, a similar proportion of vobarilizumab-treated patients achieved ACR20 response at week 12 compared with tocilizumab (73–81% versus 78%). Although more patients achieved DAS remission on highest vobarilizumab dose (225 mg every other week), when using more stringent CDAI and SDAI remission criteria, a similar efficacy was obtained in the monotherapy with vobarilizumab (5–10%) and tocilizumab groups (9–11%).

Remtolumab (ABT-122), developed by AbbVie, is another bispecific antibody, a full-length IgG with dual-variable domains (DVD-Ig), targeting two important human cytokines: TNF and IL-17A. Based on a TNF-transgenic mouse model of arthritis, dual inhibition of both cytokines proved to be more effective in suppressing inflammation and bone/cartilage destruction than either cytokine inhibitor alone⁶⁷. However, a phase II trial demonstrated that a strategy of dual inhibition of TNF and IL-17A with remtolumab does not appear to be significantly different from that of TNF inhibition alone with adalimumab in human patients with RA and psoriatic arthritis⁶⁸. In addition to this finding, recent data proved that another DVD-Ig lutikizumab (ABT-981) targeting IL-1α/β did not improve pain or synovitis in patients with both erosive hand osteoarthritis and knee osteoarthritis^69,70.

Conclusion

Biologicals have become an essential part of the therapeutic armamentarium for RA, significantly ameliorating disease activity and improving quality of life. Furthermore, the progress in our understanding of the pathogenesis of RA has significantly contributed to the development of novel intracellular targeted therapies such as JAK inhibitors tofacitinib and baricitinib that have already been implemented in routine clinical practice. Nowadays, more selective JAK inhibitors and other targeted synthetic therapies are in various stages of clinical development in RA, which is beyond the scope of this review and is reported elsewhere^71,72. In addition to the development of new therapies, the patent protection of older original biological agents expires and biosimilars have been entering the market within the last few years, thus lowering the price and enabling the treatment of more patients⁷³.

Despite current practice, early and intensive management with the treat-to-target approach, reaching remission is still not achieved in most patients, which is one of the driving forces behind the continuous development of novel therapies and the optimization of therapeutic strategies⁷⁴. Thus, advances in antibody engineering and further therapeutic targets such as neuro-immune modulation, gene therapy, and epigenetic modification are being evaluated in the treatment of RA^75–77. In addition, the two main treatment strategies can be potentially applied in the future to improve disease outcome, halt further progression, or even cure the disease either 1) by an induction-maintenance regime with biological therapies administered as early as the diagnosis is established⁷⁸ or 2) even before clinical arthritis becomes apparent⁷⁹. Currently, several ongoing proof-of-concept trials are testing whether targeting T-cells or B-cells can induce immunological reset and be used to prevent the onset of RA⁸⁰. An advanced study demonstrated that a single infusion of 1,000 mg rituximab significantly delayed the development of arthritis in patients at risk of developing of RA⁸¹. Other treatment approaches for preventive strategies may represent, for instance, the use of tolerogenic dendritic cells⁸² or targeting the IL-17/23 axis⁸³ in order to block arthritis development in pre-clinical phases of the disease. However, further research is needed to determine which therapeutic agent or strategy would best suit each individual patient.