Combination Therapies in the Context of Anti-CD3 Antibodies for the Treatment of Autoimmune Diseases
Total Page：16
File Type：pdf, Size：1020Kb
Review article | Published 28 November 2012, doi:10.4414/smw.2012.13711 Cite this as: Swiss Med Wkly. 2012;142:w13711 Combination therapies in the context of anti-CD3 antibodies for the treatment of autoimmune diseases Yann Dean, Fabien Dépis, Marie Kosco-Vilbois NovImmune SA, Plan-Les-Ouates, Switzerland Summary against the epsilon chain of the CD3-TCR complex, which is expressed on mature T cells. Muromomab exerts po- Non-Fc receptor binding anti-CD3 antibodies are in clinic- tent immunosuppressive effects via two mechanisms, (1.) T al development for the treatment of autoimmune diseases. cells are transiently eliminated from the circulation as a res- Results from phase 1/2 clinical trials suggest that teplizu- ult of cell margination and cell death, while a fraction of T mab and otelixizumab preserve residual beta-cell function cells are actually depleted in tissues, and (2.) remaining and in patients with recent onset type 1 diabetes. Similarly, en- re-appearing T cells transiently persist as CD3-TCR negat- couraging results from phase 1/2 clinical trials have been ive (a phenomenon termed antigenic modulation) and thus reported for visilizumab and foralumab in patients with in- are unable to form an immune synapse with cells present- flammatory bowel disease. However, these CD3-directed ing antigenic peptides. The outcome of antigenic modu- therapies have recently suffered setbacks due to the repor- lation is that T cells can no longer be triggered by the ted inefficacy results observed during phase 2/3 clinical transplanted alloantigens. T cell function returns to nor- trials due to low dosages or inappropriate clinical end- mal within days after cessation of antibody administration. points. Due to adverse events observed in the phase 1/2 pi- Randomised clinical trials have shown that muromonab ef- lot trials, the dose of anti-CD3 antibodies was reduced in fectively treats acute renal allograft rejection [1]. In addi- the phase 2/3 confirmatory trials. Thus, these studies reveal tion, it has also been used successfully to treat acute rejec- a narrow therapeutic window of anti-CD3-based therapies tion in liver and heart transplant recipients [1]. in which low doses are ineffective and higher pharmaco- Anti-CD3 mAbs are administered clinically once a day for logically active doses cause intolerable levels of adverse several consecutive days. Muromomab is of murine ori- effects. Combining anti-CD3 antibodies with other drugs gin and highly immunogenic in humans. Most patients pro- may be the most effective way to reduce toxicity while al- duce high titre anti-mouse antibodies following a course lowing significant therapeutic benefit. Indeed, monother- of treatment. In addition, muromonab is associated with apy also has its limits from the perspective of targeting a wide spectrum of side effects which occur almost im- only a single arm of the immune process. Notably, several mediately after administration of only the first doses [2]. recent experimental studies show potent synergy between These include flu-like symptoms such as fever, chills, naus- anti-CD3 antibodies and various therapeutic modalities for ea, vomiting and headaches. This first-dose response is the treatment of autoimmune diseases. In this review we called the “cytokine release syndrome” and occurs in al- present a review of preclinical studies evaluating combin- most all patients. Approximately 5% of patients experience ation therapies using anti-CD3 antibodies for the treatment more serious reactions, such as cardiopulmonary distress, of autoimmune diseases. seizures, encephalopathy, meningitis, renal insufficiency and graft thrombosis. The severity of these side effects Key words: anti-CD3; combination therapy; autoimmune diminishes with successive doses, due to antigenic mod- diseases ulation and T cell depletion. These unwanted effects of muromonab are a consequence of T cell activation, which Introduction results in the release of numerous cytokines into the sys- temic circulation. As T cells play a key role in the process of transplant re- To gain further insight into the mechanism of action of anti- jection through recognition of foreign antigens presented CD3 therapies, the hamster antibody 145-2C11, directed by MHC molecules expressed on antigen presenting cells against the epsilon chain of the murine CD3/TCR complex, (APC), the first therapeutic monoclonal antibody (mAb) to was developed [3]. Like muromonab, 145-2C11 induces a be approved by the FDA was an anti-T cell antibody for first dose reaction in vivo associated with the transient re- the treatment of solid-organ transplantation in 1986. Mur- lease of cytokines including tumour necrosis factor (TNF), omonab (Orthoclone OKT3®) is a mouse IgG2a directed Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 1 of 11 Review article Swiss Med Wkly. 2012;142:w13711 interferon-gamma (IFN-γ) and interleukin-2 (IL-2) [4, 5]. have immunosuppressive properties similar to that of mur- In addition, in mice, 145-2C11 induces transient antigen- omonab while they do not have its severe unwanted im- ic modulation, elimination of T cells from the circulation mune activating capacity. Furthermore, using otelixizumab and T cell depletion in tissues, and prevents acute rejection in transgenic non-obese diabetic (NOD) mice expressing of fully mismatched allograft [5]. These findings show that the epsilon chain of the human CD3/TCR complex, Kuhn 145-2C11 is a surrogate molecule for muromonab, and two and colleagues have investigated the therapeutic efficacy major pharmacodynamic discoveries were in fact made us- and mechanism of action of non-FcγR binding anti-CD3 ing 145-2C11 in vivo. First, anti-CD3 mAb treatment re- therapies in T1D [10]. They showed that, similarly to that verses an ongoing autoimmune process and promotes long- of 145-2C11 in normal mice, Fc-modified anti-human CD3 term disease remission. Beyond their immunosuppressive induce durable disease remission that is dependent on properties, anti-CD3 mAbs exert potent immunoregulatory transferable T cell mediated tolerance [10]. In T1D, anti- effects via preferential killing of activated effector T cells CD3 mAbs appear to exert therapeutic effects in two con- and/or induction of transforming growth factor-beta (TGF- secutive phases. The first one, during drug exposure, in- β)-dependent adaptive regulatory T cells (Tregs) [6, 7]. Se- volves alteration in the circulation of T cells and T cell un- cond, the ‘anti-CD3-induced first dose reaction’, associated responsiveness as a consequence of antigenic modulation with cytokine release, is mainly due to binding of the crys- as well as killing of a fraction of T cells by apoptosis. The tallizable fragment (Fc) to Fc gamma receptor (FcγR)-bear- second phase starts when the antibody has cleared from ing leukocytes, since anti-CD3 mAbs without Fc or bearing the circulation; it involves re-expression of CD3/TCR com- a Fc with reduced capacity to bind FcγRs remain immun- plexes on remaining T cells with enrichment for protect- osuppressive and capable of inducing long lasting tolerance ive TGF-β dependent adaptive Tregs. Tregs appear more [8]. resistant to apoptosis induced by non-FcγR binding anti- CD3 antibodies compared with both recently activated ef- New generation of CD3-directed fector and naive T cells [11]. Non-FcγR binding anti-CD3 therapies therapies are being developed for the treatment of various autoimmune diseases (table 1). Due to its efficacy and although it provokes severe side ef- fects, muromonab has been used extensively in the field of transplantation. In addition to allograft rejection, T cells Fc-modified anti-human CD3 mAbs in play a key role in the pathogenesis of many autoimmune autoimmunity diseases including multiple sclerosis, type-1 diabetes (T1D), inflammatory bowel disease (IBD), psoriasis and Anti-CD3 therapy for the treatment of T1D rheumatoid arthritis. Hence in the early nineties mur- Phase 1/2 clinical trials have been conducted to investigate omonab was also administered to patients with severe mul- the capacity of teplizumab and otelixizumab to suppress tiple sclerosis [9]. However, due to its toxicity, develop- the autoimmune process and preserve the residual β-cell ment for the treatment of autoimmune diseases with this function in patients with new onset T1D. The first antibody, anti-CD3 mAb was stopped. teplizumab, was investigated in 24 patients in whom the To alter the risk-to-benefit ratio and thus allow assessment disease had been diagnosed within the previous six weeks of CD3-directed therapies for the treatment of autoimmune [12]. In this open label study, patients were randomised to diseases, several Fc-modified anti-human CD3ԑ mAbs receive a single 14-day course of daily infusions with tepli- were created, including humanised versions of rodent anti- zumab (34 mg cumulative dose for a patient weighing 70 human CD3 mAbs (visilizumab, teplizumab, otelixizumab) kg) or no antibody treatment, and were followed for one and fully human mAb (foralumab). These mAbs have a year. Nine of the twelve patients, treated with the therapeut- similar engineered element built into their Fc portion. ic mAb, maintained or increased insulin production in re- Amino acid mutations are introduced into the second heavy sponse to a mix meal after one year, while only two out of constant domain in order to reduce FcγR binding and the twelve control patients had a sustained response. The most resultant cytokine release associated with cross-linking of frequent side