Immunotherapy in type 1 Diabetes

Immunotherapies currently in development for the
treatment 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 by
macrophages and dendritic cells
APCs present to CD4+ T cells which release cytokines
A cascade of immune attack follows which ultimately results
in type 1 DM
Immunotherapies aﬀect steps in this process

Protective mechanisms
T cells have TCRs which recognize native and foreign antigens
presented by the APCs
Central tolerance in the thymus ensures apoptosis of
autoreactive T cells, but some T cells escape
Tregs control these escaped autoreactive T cells
Peripheral tolerance or defective central deletion of
diabetogenic T cells can result in T1DM

Immune Tolerance

Tregs and CTLA4

Challenges- Epitope Spreading

Challenges- Timing

Goals of immunotherapy
1 Slowing the progression of disease
2 Stopping the process of insulitis indeﬁnitely
3 Restoring self tolerance

Pharmacological immune suppression
Started with development of cyclosporine in 1980s
Pharmacologic strategies currently in use
Antigen speciﬁc therapies
Monoclonal antibodies
Fusion proteins
Alternate Treg aﬀectors

Immunosuppression- How speciﬁc and how much?

Antigen speciﬁc immunotherapies
Aims to achieve anergy in T cells
The same proteins that cause immune response result in
anergy

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 recent
onset T1DM received two, subcutaneous injections of 20 µg
of GAD-alum treatment or placebo
NO change in C peptide at 15 months, signiﬁcantly diﬀerent
from placebo at 30 months

Glutamic acid decarboxylase
Could not be replicated in the phase III trial
No signiﬁcant diﬀerence in glycated hemoglobin, daily insulin
dose or any other secondary outcomes

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 the
placebo group developed T1DM
Post-hoc subgroup analysis revealed that oral insulin delayed
diabetes onset for up to 5 years in patients with high-titer
insulin antibodies

Insulin
In phase I trial by Orban et al, oral insulin, despite inducing
IL-10 producing Tregs, could not prevent progression of
diabetes
Neither oral nor nasal administration of insulin had eﬀect on
progression to type 1 diabetes

Heat shock protein 60
HSP 60 is expressed in β cells
Diapep277, which is a short 24 amino acid peptide that stems
from human HSP60, has been tested on both NOD mice and
humans as a potential ASI
Authors retracted the phase III trial and no further trial in
pipeline

CD3 and CD28-CD80/86 costimulation

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 low
dose
No signiﬁcant diﬀerence between the groups

Teplizumab
AbATE study showed a signiﬁcant preservation in C-peptide
for up to 2 years
Two courses of teplizumab or placebo were administered
shortly after diagnosis and again after 1 year to 52 T1DM
patients
Patients treated with teplizumab had a 75% reduced decline
in C-peptide at 2 years (-0.28 nmol/l vs control -0.46 nmol/l,
p = 0.002)

Otelixuzumab
anti-CD3 monoclonal antibody
In a large randomized Phase III trial Defend 1, a cumulative
3.1 mg dose of otelixizumab did not preserve C-peptide or
other markers of metabolic control in 281 recent onset
patients
Distinct risk/benefit profile for anti-CD3 therapeutics with
greater doses providing a longer slowing of the autoimmune
attack for up to 4 years but at the price of more severe side
effects

Rituximab
anti CD20 antibody, depletes B cells
A 1-year study of 87 patients with recent onset T1DM had
the defined primary end point of mean Cpeptide, which was
significantly better in the rituximab group vs placebo: 0.56
and 0.47 nmol/l, respectively (percentage difference 20%; p =
0.03)
At 2 years difference had vanished

Canakinumab (and Anakinra)
IL-1 causes β-cell dysfunction and destruction via the NFkB
and MAPK pathways
IL-1 is released locally by the β cells during hyperglycemia,
which then inhibits insulin synthesis and release and causes
apoptosis of β cells via the Fas receptor
Canakinumab is a human monoclonal anti-IL-1 antibody
Phase II trials showed neither Anakinra nor Canakinumab are
useful for halting the immune attack on β cells

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 in
autoimmune attack on the β cells

Fusion proteins
Fusion proteins are composed of an immunoglobulin Fc
domain directly linked to another protein
The fused peptide can serve as a ligand that activates when
received by a cellsurface receptor, an antigen (Ag) or as a
binding protein

Abatacept
Fusion protein created to curb T cells co-stimulatory signal
interceded through the CD28-CD80/86 pathway
Obstructs the early stages of T-cell activation, production and
continued 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 or
neutropenia
Return to inexorable decline in β cell function

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 highly
pathogenic effecter and memory T cells (CD4+ Tcm cells
decreased by 25 – 30% and CD4+ Tem cells decreased by 40
– 60%)
Promising treatment due to its demonstrated preservation of
Treg/Teff balance

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 of
3IU/day(max)
Persistent increase in IL2 at 60 days and improvement in
Treg/Teﬀ balance

Lessons . . .
No single therapeutic gent provides a lasting halt of the
immune 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 insulin
Enrolled within 6 weeks of diagnosis of T1DM
C-peptide mean AUC > 0.2 nmol/l

Lessons . . .
High cumulative doses of monoclonal antibodies can have β
cell protective eﬀects upto 4 years
Combination therapies to be evaluated, but caution to be
maintained
Combination of rapamycin(mTOR inhibitor) which decreases
Teﬀs and IL2 which increases Tregs resulted in transient
decline in β cell function
Ideal timing and dosing are not known

Conclusion
Currently immunotherapy has limited role in the management of
Type 1 Diabetes

Thank You

Table: Some
useful caption
One Two
Three 1 Four
1 The ﬁrst
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Immunotherapy in type 1 Diabetes

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