Immunotherapies currently in development for thetreatment of type 1 diabetes

Ian C Davis, Jacqueline Randell & Stephen N Davis

Expert Opinion on Investigational Drugs, 24:10, 1331-1341

Karthik Balachandran Immunotherapy in T1DM

Background

Autoantigens released from β cells prompt infiltration bymacrophages and dendritic cells

APCs present to CD4+ T cells which release cytokines

A cascade of immune attack follows which ultimately resultsin type 1 DM

Immunotherapies affect steps in this process

Karthik Balachandran Immunotherapy in T1DM

Protective mechanisms

T cells have TCRs which recognize native and foreign antigenspresented by the APCs

Central tolerance in the thymus ensures apoptosis ofautoreactive T cells, but some T cells escape

Tregs control these escaped autoreactive T cells

Peripheral tolerance or defective central deletion ofdiabetogenic T cells can result in T1DM

Karthik Balachandran Immunotherapy in T1DM

Immune Tolerance

Karthik Balachandran Immunotherapy in T1DM

Tregs and CTLA4

Karthik Balachandran Immunotherapy in T1DM

Tregs and CTLA4

Karthik Balachandran Immunotherapy in T1DM

Challenges- Epitope Spreading

Karthik Balachandran Immunotherapy in T1DM

Challenges- Timing

Karthik Balachandran Immunotherapy in T1DM

Goals of immunotherapy

1 Slowing the progression of disease

2 Stopping the process of insulitis indefinitely

3 Restoring self tolerance

Karthik Balachandran Immunotherapy in T1DM

Pharmacological immune suppression

Started with development of cyclosporine in 1980s

Pharmacologic strategies currently in use

Antigen specific therapiesMonoclonal antibodiesFusion proteinsAlternate Treg affectors

Karthik Balachandran Immunotherapy in T1DM

Immunosuppression- How specific and how much?

Karthik Balachandran Immunotherapy in T1DM

Antigen specific immunotherapies

Aims to achieve anergy in T cells

The same proteins that cause immune response result inanergy

Karthik Balachandran Immunotherapy in T1DM

Glutamic acid decarboxylase

Triggers glutamate conversion to GABA

GAD65 vaccines potential to halt progression of diabetes

Moderate success in human trials

Phase II trial by Ludvigsson et al., 118 patients with recentonset T1DM received two, subcutaneous injections of 20 µgof GAD-alum treatment or placebo

NO change in C peptide at 15 months, significantly differentfrom placebo at 30 months

Karthik Balachandran Immunotherapy in T1DM

Glutamic acid decarboxylase

Could not be replicated in the phase III trial

No significant difference in glycated hemoglobin, daily insulindose or any other secondary outcomes

Karthik Balachandran Immunotherapy in T1DM

Insulin

Skyler et al - DPT1

Low dose of oral insulin to first-degree relatives of T1DM

372 patients studied, 44 in the oral insulin group and 53 in theplacebo group developed T1DM

Post-hoc subgroup analysis revealed that oral insulin delayeddiabetes onset for up to 5 years in patients with high-titerinsulin antibodies

Karthik Balachandran Immunotherapy in T1DM

Insulin

In phase I trial by Orban et al, oral insulin, despite inducingIL-10 producing Tregs, could not prevent progression ofdiabetes

Neither oral nor nasal administration of insulin had effect onprogression to type 1 diabetes

Karthik Balachandran Immunotherapy in T1DM

Heat shock protein 60

HSP 60 is expressed in β cells

Diapep277, which is a short 24 amino acid peptide that stemsfrom human HSP60, has been tested on both NOD mice andhumans as a potential ASI

Authors retracted the phase III trial and no further trial inpipeline

Karthik Balachandran Immunotherapy in T1DM

CD3 and CD28-CD80/86 costimulation

Karthik Balachandran Immunotherapy in T1DM

Monoclonal antibodies - Teplizumab

Humanized, anti-CD3 monoclonal antibody

Protege and Abate trials

Protege - 513 type 1 diabetes patient, primary end point-insulin use < 0.5u/kg/day and HbA1c < 6.5%

Four groups - 14 day high and low dose, 6 day high and lowdose

No significant difference between the groups

Karthik Balachandran Immunotherapy in T1DM

Teplizumab

AbATE study showed a significant preservation in C-peptidefor up to 2 years

Two courses of teplizumab or placebo were administeredshortly after diagnosis and again after 1 year to 52 T1DMpatients

Patients treated with teplizumab had a 75% reduced declinein C-peptide at 2 years (-0.28 nmol/l vs control -0.46 nmol/l,p = 0.002)

Karthik Balachandran Immunotherapy in T1DM

Otelixuzumab

anti-CD3 monoclonal antibody

In a large randomized Phase III trial Defend 1, a cumulative3.1 mg dose of otelixizumab did not preserve C-peptide orother markers of metabolic control in 281 recent onsetpatients

Distinct risk/benefit profile for anti-CD3 therapeutics withgreater doses providing a longer slowing of the autoimmuneattack for up to 4 years but at the price of more severe sideeffects

Karthik Balachandran Immunotherapy in T1DM

Rituximab

anti CD20 antibody, depletes B cells

A 1-year study of 87 patients with recent onset T1DM hadthe defined primary end point of mean Cpeptide, which wassignificantly better in the rituximab group vs placebo: 0.56and 0.47 nmol/l, respectively (percentage difference 20%; p =0.03)

At 2 years difference had vanished

Karthik Balachandran Immunotherapy in T1DM

Canakinumab (and Anakinra)

IL-1 causes β-cell dysfunction and destruction via the NFkBand MAPK pathways

IL-1 is released locally by the β cells during hyperglycemia,which then inhibits insulin synthesis and release and causesapoptosis of β cells via the Fas receptor

Canakinumab is a human monoclonal anti-IL-1 antibody

Phase II trials showed neither Anakinra nor Canakinumab areuseful for halting the immune attack on β cells

Karthik Balachandran Immunotherapy in T1DM

Gevokizumab

Antibody against IL-1β

Shown in type 2 diabetes to be well tolerated and efficacious

IL-1β has role in both type 1 and type 2 diabetes

None of the antibodies have shown durable reduction inautoimmune attack on the β cells

Karthik Balachandran Immunotherapy in T1DM

Fusion proteins

Fusion proteins are composed of an immunoglobulin Fcdomain directly linked to another protein

The fused peptide can serve as a ligand that activates whenreceived by a cellsurface receptor, an antigen (Ag) or as abinding protein

Karthik Balachandran Immunotherapy in T1DM

Abatacept

Fusion protein created to curb T cells co-stimulatory signalinterceded through the CD28-CD80/86 pathway

Obstructs the early stages of T-cell activation, production andcontinued existence

Phase II trial involving 103 patients

Defers immune attack for an average of 9.6 months

Well tolerated, no increased risk of EBV infection orneutropenia

Return to inexorable decline in β cell function

Karthik Balachandran Immunotherapy in T1DM

Alefacept

Dimeric fusion protein blocking T cell costimulation

alefacept had a positive effect on preserving b-cell function,which investigators attribute to the depletion of highlypathogenic effecter and memory T cells (CD4+ Tcm cellsdecreased by 25 – 30% and CD4+ Tem cells decreased by 40– 60%)

Promising treatment due to its demonstrated preservation ofTreg/Teff balance

Karthik Balachandran Immunotherapy in T1DM

Other T reg affectors

IL2 improves Tregs

Low dose IL2 prevents and treats type 1 DM in NOD mice

Adult patients tolerate IL2 at tested dose levels of3IU/day(max)

Persistent increase in IL2 at 60 days and improvement inTreg/Teff balance

Karthik Balachandran Immunotherapy in T1DM

Lessons . . .

No single therapeutic gent provides a lasting halt of theimmune attack and remission of the T1DM phenotype

Responders in Abate and Protege trials

Younger (8-17 years)HbA1c < 7.5%Used < 0.4U/kg/d of insulinEnrolled within 6 weeks of diagnosis of T1DMC-peptide mean AUC > 0.2 nmol/l

Karthik Balachandran Immunotherapy in T1DM

Lessons . . .

High cumulative doses of monoclonal antibodies can have βcell protective effects upto 4 years

Combination therapies to be evaluated, but caution to bemaintained

Combination of rapamycin(mTOR inhibitor) which decreasesTeffs and IL2 which increases Tregs resulted in transientdecline in β cell function

Ideal timing and dosing are not known

Karthik Balachandran Immunotherapy in T1DM

Conclusion

Currently immunotherapy has limited role in the management ofType 1 Diabetes

Karthik Balachandran Immunotherapy in T1DM

Thank You

Karthik Balachandran Immunotherapy in T1DM

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Karthik Balachandran Immunotherapy in T1DM