Table 1 Characteristics of included studies

Tooley et al.

2016

2 randomized clinical studies: AbATE trial and Delay trial

125 + 53 = 183

Study size from 2 Kevan Herold study

Clinical responders showed a significant reduction in circulating CD4 + effector memory T cells. Afterward, there was an increase in the frequency and absolute number of CD8CM

T cells. BY 2 months:

In AbATE trial: (responder: 14.6 ± 2.16% vs. nonresponder: 10.6 ± 1.5%, p = 0.13)

In Delay trial: (10.0 ± 1.41 vs. 6.25 ± 1.23%, p = 0.046).

In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of

non-CM T cells.

Nil

-Nanostring analysis of gene expression of CD8CM T cells from responders and non responders versus placebo-treated control subjects identified decreases in

expression of genes associated with immune activation and increases in expression of

genes associated with T-cell differentiation and regulation.

- CD8CM T cells with decreased activation and regulatory gene expression are associated with

clinical responses to teplizumab in patients with T1D

Nicole Sherry et al.

2011

2-year trial (protégé study)

763

Teplizumab had a

treatment effect on C-peptide and insulin use while maintaining glycaemic control, particularly in selected,

prespecified subgroups 54.39%(415), and exemplifies the risks of

developing a new outcome without previous validation

77% (318/415) of patients treated with teplizumab

(150/207 [72%] in the 14-day full-dose group, 78/102 [76%]

in the 14-day low dose group, and 90/106 [85%] in the

6-day full-dose group) and 13% (13/98) of those receiving

placebo developed anti-drug antibodies.

- Across the four study groups, similar proportions of patients had

adverse events (414/417 [99%] in the teplizumab groups vs. 98/99 [99%] in the placebo group) and serious adverse

events (42/417 [10%] vs. 9/99 [9%])

Alice Long et al.

2017

AbATE clinical trial

15

Treatment with teplizumab leads to a transient reduction

of CD3-positive cells from peripheral blood, its more durable effects

correspond to an agonist activity that induces markers reminiscent of

hyporesponsive cells

Nil

- The primary clinical outcome was the preservation of plasma C-peptide two years after initiation of the study measured as a 4-h MMTT-stimulated C-peptide AUC.

- Teplizumab increases proportions of central memory cells and cells

displaying an exhausted phenotype in circulating CD8 T cell

- Teplizumab modulates CD127 expression in circulating CD8 T cell

Subsets.

- Teplizumab increases proportions of effector memory and PD-1 + cells

in circulating CD4 T cells

-The observed phenotypic changes across cell

types were associated with favorable responses to treatment in the subgroup of study participants who did not

develop anti-drug antibodies after the first course of therapy

Jasmin Lebastchi et al.

2013

Clinical trial

93

Higher rates of b-cell death in patients with recent-onset T1D 46.23%(43) versus nondiabetic control subjects 13.98% (13) and have shown that teplizumab treatment is associated with reduced level of b-cell death.

Nil

The levels of unmethylated INS

DNA are elevated in subjects with new-onset T1D compared with nondiabetic control subjects and suggest active

b-cell destruction at the time of onset of disease.

Kevan C Herold et al.

2013

randomized, open-labeled, controlled

trial.

125

− 2 courses of treatment with FcR nonbinding anti-CD3 mAb (teplizumab) reduced the loss of C-peptide 2 years after the first

treatment in patients with new-onset T1D. (52)(p = 0.002)

- teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D

Nil

- There was a significant reduction in the titer of

anti-ZnT8 antibodies b

ut not the other biochemical autoantibodies in the drug-treated group at

the end of year 1 (p < 0.05) and the differences at 2 years were not statistically significant

- There was a total of 11 serious adverse events (SAEs) in 10 drug-treated subjects and

2 SAEs in 1 control subject

- clinical responders had lower HbA1c levels while the non-responders does not(received same amount of drugs).

Kevan C. Herold et al.

2009

randomized, open labeled phase IIb trial

10

Study supports previous investigations

showing that treatment of patients with new onset T1DM

with a brief course of teplizumab results in a reduced rate of

decline in insulin production and a decrease in insulin

requirements for more than 2 years after diagnosis. A

higher dose of drug, approximately 40% higher than the

dose used previously, resulted in increased AEs

Nil

- Teplizumab caused transient reduction in circulating T cells, but the recovered cells were not new thymic emigrants because T cell receptor excision circles were not

increased.

- increased adverse events due to increase dose

- There was a trend for reduced loss of C-peptide over 2 years with drug treatment

(p = 0.1), and insulin use was lower (pb0.001)

- Anti-CD3 mAbs may prolong β cell function up to 2 years in patients with new onset

Type 1 diabetes (T1DM).

Ana Luisa Perdigoto et al.

2018

Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial

77

C-peptide and T cell markers of

response remain in individuals with type 1 diabetes, who were

treated with teplizumab, for more than 7 years after diagnosis.

Major adverse events were captured at the time of

the follow-up visit

- Drug-treated responders showed a significantly increased frequency of programmed cell death protein 1-positive central

memory and anergic CD8 + T cells at follow-up

- the drug-treated responders demonstrated a significantly greater C-peptide response than the control group and

drug-treated non-responders

- Insulin use and

HbA1c levels were significantly lower in the drug-treated responders than in the drug-treated non-responders or control

participants at visits during the first 2 years but not at the

follow-up visit

- There was a modest inverse relationship between the C-peptide AUC and daily insulin use

- The titres of anti-ZnT8

(p < 0.01) and IA-2 antibodies (p < 0.001) declined but MIAA

(p < 0.001) increased over time. The titres of

anti-GAD65 antibody did not change significantly.

Kevan C. Herold et al.

2019

phase 2, randomized, placebo-controlled, double-blind trial of teplizumab

76

2-week course of

treatment with teplizumab delayed the diagnosis of clinical type 1 diabetes in high-risk participant.

-a 2-week course of

treatment with teplizumab delayed the diagnosis of clinical type 1 diabetes in high-risk participant; 19 (43%) of the 44 participants who received teplizumab and 23 (72%) of the 32 participants who received placebo had type 1 diabetes diagnosed.

- Teplizumab treatment was associated with adverse events but we’re all later resolve except in one person(Lymphopenia)

-Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants.

- There were expected adverse events of rash and transient lymphopenia.

- The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs.

placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006

- The annualized rates of diagnosis of diabetes were

14.9% per year in the teplizumab group and 35.9% per year in the placebo group.

K. C. Herold et al.

2013

a randomised placebo-controlled trial

58

-The teplizumab group lost significantly less C-peptide at 12 months as a percentage of the C-peptide at baseline (18% [95% CI 7.43, 28.5] vs.

39.0% [95% CI 27.8%, 50.2%], p00.006). At 12 months, five of the 58 participants did not have detectable C-peptide

-Teplizumab treatment

had no significant effect on the HbA1c levels or on change in

the HbA1c levels over the 12-month study period

All adverse events were resolved

- significant increase in CD8CM

T cells at month 2 in teplizumab clinical responders compared

with teplizumab non-responders (p00.018)

-There was a significant difference in the responses of younger

(age < 15 years) and older participants (≥ 15 years) (p00.047).

When corrected for baseline C-peptide and HbA1c levels,

teplizumab-treated younger participants had C-peptide

responses that were 31.7% higher than placebo (p00.02)

whereas the teplizumab-treated older participants showed no

difference (p00.56)