Anti-CD3 mAbs for treatment of type 1 diabetes

DIABETES/METABOLISM RESEARCH AND REVIEWS R E V I E W A R T I C L EDiabetes Metab Res Rev 2009; 25: 302–306.Published online 24 March 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.933

Anti-CD3 mAbs for treatment of type 1 diabetes

Adam Kaufman andKevan C. Herold*

Department of Immunobiology, YaleUniversity, New Haven, CT 06520,USA

*Correspondence to:Dr Kevan C. Herold, Yale University,10 Amistad St, 131D, New Haven,CT 06520, USA.E-mail: [email protected]

Received: 2 November 2008Accepted: 22 November 2008

Summary

The use of anti-CD3 monoclonal antibodies (mAbs) has moved from thebench to the bedside. The experience with the anti-human CD3 mAb OKT3for treatment of transplant rejection identified limitations that were largelyovercome with the creation of humanized non-FcR binding antibodies:Teplizumab, Otelixizumab and Visilizumab. Preclinical studies showed theability of the drugs to reverse hyperglycaemia in diabetic non-obese diabetic(NOD) mice providing rationale for clinical trials with the agents. The formertwo drugs have been tested in subjects with new onset type 1 diabetes. Theyhave both shown, in randomized clinical trials, an ability to reduce the lossof insulin production over the first 2 years of the disease. In addition, theneed for exogenous insulin to maintain glucose control has been reduced.However, these agents alone do not restore normal glucose control, and futureapproaches will likely require combinations of agents with complementaryimmune or metabolic activity. Copyright 2009 John Wiley & Sons, Ltd.

Keywords type 1 diabetes; anti-CD3 antibody; immune modulation; immuno-logic tolerence

Type 1 diabetes mellitus (T1DM) is a chronic and progressive autoimmunedisease stemming from an inability of the body to properly distinguish selffrom non-self [1]. Specifically, there is a misdirected T cell-mediated attackagainst pancreatic islets leading to β cell destruction and an inability tosynthesize insulin. Exogenous insulin, regrettably, is a not a cure for T1DMbut simply a stopgap. Insulin secretion is a nuanced and complex process thatis not easily recreated through exogenous administration. The ultimate goalof therapy therefore is to prevent β cell destruction by immune modulationso that clinically significant levels of exogenous insulin production aremaintained. This would consist of retraining the immune system to eliminatethe pathogenic reactivity to autoantigens while retaining a robust responseto antigenic insults. Previously, the only effective immune modulation agentswere immunosuppressants that had wide side-effect profiles and requiredcontinuous administrations of the agents [2,3]. Recently, anti-CD3 antibodieshave shown great promise in the treatment of T1DM and differ from earlierapproaches in their lasting effects on pathogenic immune responses withoutthe need for continuous immune suppression.

Background of Anti-CD3 antibodiesThe original anti-CD3 antibody used clinically was a murine monoclonalIgG2 antibody, OKT3, that was found while looking for antibodies thatwere lymphocytic mitogens [4]. CD3 is a protein complex found on thecell surface of T cells involved in transduction of the signals comingfrom the antigen receptor to start a cascade of events initiating activa-tion of the T cell. Not surprisingly, it was quickly shown that anti-CD3

Copyright 2009 John Wiley & Sons, Ltd.

Anti-CD3 mAbs for Treatment of Type 1 Diabetes 303

mAbs inhibited lysis of targets by T cells [5]. Alongwith potent mitogenic activity, OKT3 was found to be apotent inducer of cytokines, specifically, tumour necrosisfactor alpha (TNF-α), interleukin-2 (IL-2) and interferongamma (IFN-γ ) [6]. Unfortunately, the toxicity of OKT3became abundantly clear after patients receiving the drugimmediately developed chills, fever, hypotension, andin some cases, dyspnea [7]. This toxicity was thoughtto be derived from the enormous release of cytokines,particularly TNF-α from T cells in response to the drug[8–10]. This effect was attributed to the cross-linking ofT cells bearing CD3 molecules and FcR bearing cellsthat bind to the Fc portion of the antibodies. Thiscross-linking was thought to be able to activate boththe T cell and the FcR bearing cells leading to themassive release of cytokines as previously mentioned.To confirm this, a number of studies were done inmice with F(ab′)2 fragments of anti-CD3 mAbs, whichshowed reduced potency of T cell activation, as wellas mutations of anti-human CD3 mAbs which werecreated to have reduced mitogenicity [11–14]. Parlevietshowed that using an IgA isotype of OKT3, FcR bindingand T cell activation were reduced [15]. The reducedactivation led to fewer side effects in the chimpanzeesthat were administered the drug. Furthermore, it wasshown that in vitro T cells would not expand or becomeactivated in the presence of soluble anti-CD3 antibodiesalone.

Experience with anti-CD3 mAbs intransplant rejection and autoimmunediseases

Anti-CD3 antibodies have been in use for over two decadesfor treatment of renal allograft rejection. OKT3 wasoriginally shown to reverse acute rejection of cadavericrenal allografts, refractory to conventional treatment[16]. Later, the efficacy of OKT3 for treatment of chronicrejection was also shown, but some reports have failedto show long-term improvement with the addition ofthe anti-CD3 mAb [17–20]. Likewise, anti-CD3 antibodycontinues to be useful for treatment of acute rejection ofheart and liver grafts despite mixed reports of efficacyin individual studies [21–23]. Importantly, these studieshave highlighted the risk of lymphoma, some of whichare Epstein–Barr virus (EBV) related, and malignancies inpatients treated with multiple immune suppressive agentsincluding OKT3.

OKT3 has also shown efficacy in treatment of viralmyocarditis that is thought to have an autoimmune com-ponent. In a report of five pediatric patients presentingwith congestive heart failure with ejection fractions rang-ing from 5 to 20% secondary to viral myocarditis, all fivepatients vastly improved their ejection fractions between50 and 74% with treatment with the combination ofazathioprine, cyclosporine A and OKT3 [24].

The need for change

The initial experience with OKT3 in immune suppressedpatients identified a number of problems that precludedits application for treatment of patients with T1DMincluding cytokine release syndrome and a human anti-murine antibody response [10,25–27]. To eliminate theseproblems, new mAbs were engineered: Hu291 (PDL),ChAglyCD3 (H Waldmann) and hOKT3γ 1(Ala-Ala) (JBluestone and Johnson and Johnson) [28–31]. All threemAbs are humanized and have reduced FcR binding asa result of amino acid substitutions in the Fc portions ofthe Ig molecules. While the reduced FcR binding waspredicted to eliminate T cell activation and cytokinerelease, the mAbs have not been non-mitogenic. T cellproliferation can be shown in vitro (at a 4 log reducedpotency compared to OKT3) and even mild cytokinerelease has been seen [32,33]. Indeed, the actions ofHu291 are best described as a partial agonist of T cellsignaling [34]. However, it is important to recognize thatthe anti-CD3 mAbs differ greatly in their induction of Tcell activation in vivo. Nonetheless, the changes in potencyof the antibodies compared to OKT3 significantly reducedadverse events.

Initial reports of the effects of Hu291 in acute steroidrefractory Graft vs. host disease (GVHD) and ulcerativecolitis were encouraging [35]. However, EBV copiesincreased significantly in subjects with GVHD who werereceiving other immune modulators. In ulcerative colitis,cytokine release was seen in the majority of patientsbut there were no lymphoproliferative events and <1%serious infections. HOKT3γ 1(Ala-Ala) was tested initiallyin a trial of acute graft renal and pancreas/renal allograftrejection in addition to standard therapy. Five of sevenpatients with rejection (Banff grade I–III) showed clinicalresponse to treatment [36]. In a trial of hOKT3γ 1(Ala-Ala) as a single agent in refractory psoriatic arthritis, 6/7pts who completed the trial had dramatic improvementin the number of tender and swollen joints. Five had noswollen joints at 30 days [37]. Hering et al. performedislet transplants in six subjects using Sirolimus andTacrolimus with hOKT3γ 1(Ala-Ala) [38]. Four of sixsubjects became insulin independent for up to 365 daysand severe hypoglycaemia was eliminated in all subjects.

Anti-CD3 antibodies in T1DM

The earliest work linking modified anti-CD3 antibodieswith a protective effect in diabetes was in multi-doseStreptozotocin-induced diabetes in CD-1 mice treatedwith either whole antibody or F(ab′)2 fragments ofmAb 145-2Cll [39]. The modified anti-CD3 mAb wasas effective as whole mAb but had reduced morbidity andT cell activation in vivo. Chatenoud et al. found that whenNOD mice that had spontaneously developed diabeteswere treated with 5 µg of anti-CD3 antibody per day for5 days, 64–80% of the mice returned to a euglycemic

Copyright 2009 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2009; 25: 302–306.DOI: 10.1002/dmrr

304 A. Kaufman and K. C. Herold

state without glycosuria while none of the NOD micetreated with hamster immunoglobin recovered [40–42].Moreover, when syngeneic islets were transplanted intothe mice that did not recover, all the transplantedislets in the anti-CD3-treated mice survived and restorednormal metabolic control while those transplanted intothe control group were eliminated within 4 days. TheNOD mice that were in remission successfully rejectedallogeneic skin grafts indicating that their immune systemwas intact and that beta cell-specific immune responseswere affected. Moreover, NOD mice that had recoveredafter the anti-CD3 treatment were resistant to adoptivetransfer of diabetogenic T cells.

These findings were important for at least two reasons.First, it suggested that even at the time of presentationwith hyperglycaemia, significant β cell mass remained asto warrant a therapeutic intervention, and second, thatanti-CD3 mAb could induce tolerance: The drug couldbe administered for just 5 days with a lasting effect onimmune responses. Continuous immune suppression didnot appear to be involved but the mechanism of actionwas not clear.

These preclinical studies led to two clinical trials. In thefirst, with hOKT3γ 1(Ala-Ala)(Teplizumab), 40 subjectswith new onset T1DM were randomly assigned to receive a12–14 day of the drug (based on doses used for renal andrenal/pancreas rejection) or to a control group [43,44].This study enrolled subjects between the ages of 7 1/2and 30 years in an open label design, and measured C-peptide responses to a mixed meal as a primary endpoint.Of 21 subjects treated with drug for 14 days within8 weeks of the diagnosis of diabetes, 15 had maintainedor improved C-peptide responses after 1 year comparedto 4/19 control subjects. Insulin usage was reduced andhaemoglobin A1c levels were also improved in the drug-treated cohort. Adverse events were generally mild – asingle serious adverse event (thrombocytopenia) resolvedwhen the drug was discontinued.

The second trial was a larger (n = 80), randomized,placebo-controlled, multicentre trial using ChAglyCD3(Otelixizumab) [45]. The drug was administered intra-venously for 6 days. Adverse events were more commonin this trial than in the trial with hOKT3γ 1(Ala-Ala) andthe rate of symptomatic EBV reactivation was higher.Unlike the previous trial, glucose control (reflected byhaemoglobin A1c levels) were matched in the drug-treated and placebo groups. To achieve this degreeof glucose control, the drug-treated group used signifi-cantly less insulin than the placebo-treated group. Insulinsecretion was also improved in the drug-treated group,consistent with the reduced insulin requirements, but thegreatest effect on insulin secretion was in the subjectsin the upper 1/2 of baseline insulin production at studyentry. The majority of patients in the top 50% of insulinsecretory responses at study entry who had been assignedto drug treatment used less than 0.25 U/kg/day of insulinto control their glucose, whereas this rate of insulin usagewas not sufficient for any patients in the control group.The difference between the treatment groups among those

in the bottom half of insulin secretory responses was muchsmaller, suggesting that the initial β cell mass or functionis a determinant of response to drug, a finding that hadbeen noted in trials of Cyclosporin A two decades earlierbut was not seen in the Teplizumab trial [2].

Mechanisms of action of non-FcRbinding anti-CD3 mAbs

Initial preclinical studies suggested that T cell activationwas involved in the immunologic effects of anti-CD3mAbs since concomitant treatment with Cyclosporin Areversed them [41]. Other murine studies have suggestedthat anti-CD3 mAb induces a subpopulation of adaptiveCD4 + CD25+ regulatory T cells that exert their immuneregulation through a TGF-β dependent mechanism [46].These Tregs differ from naturally occurring Tregs in thatthey can even be induced in CD28 deficient animals inwhich natural Tregs do not develop. The induced adaptiveTregs were most abundant in the draining lymph nodes ofthe pancreas of F(ab′)2-treated NOD mice. Other studieshave suggested that NK-T cells that produce IL-4 andIL-10 may be involved [47].

The mechanisms of modified anti-CD3 mAb in humansare not clear – the mechanisms that are not involved aremore certain. The mAbs coat and induce modulation ofthe T cell receptor but do eliminate T cells. The number ofcirculating lymphocytes declines transiently, the effectsof the mAbs do not simply involve T cell depletion.By 2 weeks after the last dose of drug, the number ofcirculation T cells recovers, on average to the level beforetreatment. In fact, in both studies in T1DM, the numberof circulating CD8+ cells increased after drug treatmentand persisted for an extended period of time [43,45].Explanations for the significance of this finding differ.Keymeulen et al. suggested that the recovering CD8+ Tcells were largely EBV reactive whereas Bisikirska et al.and Herold et al. have suggested that the mAb inducesCD8+ T cell proliferation, and noted that the increasein circulating CD8+ T cells correlated with clinicaloutcomes [33]. They also found that CD8+ cells thatare induced with Teplizumab have regulatory function.The CD8+ Tregs express Foxp3 and CTLA-4. In addition,the mAb-induced IL-10 production in some individualsand CD4 + IL-10+ T cells could be found ex vivo afterdrug treatment [32].

The uncertainties of the mechanism of action arecompounded by the absence of a biomarker of theimmunologic effects of the drug and easy access toappropriate animal models. Coating and modulationof CD3 is a direct measure of drug binding but theclinical effects last well beyond the period when this isoccurring. Preliminary studies with Class I and II tetramerssuggest that the antigen specific T cells are not depletedafter lymphocyte recovery, but further studies of thefunction of the antigen specific T cells will be neededto determine the effects of the drug on disease relevant


Anti-CD3 mAbs for Treatment of Type 1 Diabetes 305

cells. Unfortunately, only chimpanzees express a CD3molecule that is recognized by anti-human CD3 mAbs, sothat opportunities for testing hypotheses related to themAbs mechanism of action in vivo are limited.

Looking forward

Several questions remain in the application of anti-CD3 mAb for treatment of diabetes. The effect oftreatment is not permanent – studies are now in progressto determine whether an additional course of drugtreatment will maintain C-peptide responses. Second,trials of immune modulation in type 1 diabetes haveenrolled subjects generally within 3 months of diagnosis.However, clinically significant insulin production persistsin many patients for much longer periods of time. In these,as well as others, in whom insulin production is less, theability of immune modulation to stem the progression ofβ cell loss or even permit recovery of β cells has not beentested. The absence of an effect of immune modulators inpatients with more established disease would suggest thattime-limited events account for the clinical appearance ofdisease that are most amenable to immune modulation.

The proverbial ‘cure’ of type 1 diabetes is unlikely tobe based on immune modulation with a single agentbut is more likely to involve a combination of agentsthat can arrest the autoimmune destruction of β cells,perhaps by arresting multiple pathways, and stimulateregeneration and/or β cell function (Table 1). Our studiesin NOD mice treated with anti-CD3 mAb have shown thata major component of recovery of β cell function reflectsrecovery of existing β cells that are dysfunctional at thetime of presentation with hyperglycaemia rather thanregeneration or proliferation of new cells [48]. It remainsuncertain whether spontaneous β cell regeneration willoccur following immune modulation and whether thismay be augmented through pharmacologic approaches.Drugs such as Glucagon-like peptide-1 (GLP-1) receptoragonists may augment insulin content of the recoveredβ cells. Our studies and those of others have shownthat this mechanism rather than β cell proliferationaccounts for the enhanced reversal of diabetes whenanti-CD3 mAb is combined with Exendin-4 [49]. Specificimmune modulation may also be enhanced or maintainedwith combinatorial approaches such as administeringautoantigenic peptides at the time of administration ofanti-CD3 mAb [50].

Table 1. Examples of combination therapies for use withanti-CD3 mAb

Category Example Reference

B cell agents Rituxan 51Anti-inflammatory agents IL-1 receptor antagonists 52Agents that stimulate betacell function or proliferation

Exenatide 49

Antigen specific tolerance Insulin 50Tregs 53

Conclusion

In summary, preclinical and early clinical studies haveshown that a single course of treatment with anti-CD3mAb can prevent progression of type 1 diabetes over thefirst 1–2 years after diagnosis. The mechanism appears toinvolve induction of immune tolerance, possibly mediatedby regulatory T cells, rather than chronic immunesuppression. Studies to prolong the clinical effects and toestablish the optimal timing for intervention are now inprogress. The outcomes of these studies will be importantfor designing comprehensive approaches for curing thedisease.

Acknowledgements

Supported by grants: RO1 DK DK057846, JDRF 2006-351, 2007-502, and 2007-1059, UL1 RR02139 (CTSA), and gifts from theBrehm Foundation and Friends United for Diabetes Research.

Conflict of interest

None declared.

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Anti-CD3 mAbs for treatment of type 1 diabetes

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