What are the treatment options using antibodies such as teplizumab (anti-CD3 monoclonal antibody) or otelixizumab (anti-CD3 monoclonal antibody) for a patient with type 1 diabetes or at risk of developing it?

Antibody Treatment for Type 1 Diabetes

Teplizumab-mzwv is the only FDA-approved antibody therapy for type 1 diabetes and should be offered to individuals aged ≥8 years with Stage 2 type 1 diabetes to delay progression to symptomatic Stage 3 disease. 1, 2

Patient Selection Criteria

Stage 2 type 1 diabetes is defined by:

• Presence of two or more pancreatic islet autoantibodies (GAD, IAA, IA-2A, ZnT8A, or ICA) 2
• Evidence of dysglycemia on oral glucose tolerance testing 2
• No clinical symptoms of diabetes 3

The diagnosis requires confirmation through autoantibody testing followed by OGTT to demonstrate abnormal glucose metabolism without overt hyperglycemia 1.

Clinical Efficacy Data

Teplizumab doubles the time to symptomatic diabetes diagnosis:

• Median time to Stage 3 diagnosis: 48.4 months with teplizumab vs 24.4 months with placebo 1, 4
• Hazard ratio: 0.41 (95% CI 0.22-0.78; P=0.006) 1, 4
• Stage 3 diabetes developed in 43% of teplizumab-treated patients vs 72% of placebo patients 1
• Annualized progression rate: 14.9% per year with teplizumab vs 35.9% per year with placebo 4

Predictors of Superior Response

Consider teplizumab particularly strongly in patients with:

• HLA-DR4 positive (HR 0.20; 95% CI 0.09-0.45) 1
• HLA-DR3 negative (HR 0.18; 95% CI 0.07-0.45) 1
• Anti-zinc transporter 8 antibody negative (HR 0.07; 95% CI 0.02-0.26) 1

These genetic and immunologic markers identify patients who achieve the greatest delay in disease progression 1.

Treatment Administration

Dosing regimen:

• Single 14-day course of intravenous infusions 1, 2
• BSA-based dosing normalizes drug exposure across different body weights 2
• Must be administered in a facility with appropriately trained personnel capable of managing infusion reactions and immune-mediated adverse events 1, 3

The treatment course is given once, with no repeat dosing required in the pivotal trial 4.

Safety Profile and Adverse Events

Most common adverse reactions:

• Transient lymphopenia in 73% of patients, with nadir on day 5 of the 14-day course 1, 2
• Rash in 36% of patients 1
• Lymphopenia occurs without actual T-cell depletion and resolves spontaneously 2

Immunogenicity concerns:

• Approximately 57% of patients develop anti-teplizumab antibodies 2
• 46% of antibody-positive patients develop neutralizing antibodies 2
• Higher incidence of rash in patients who develop anti-drug antibodies 2

All adverse effects were primarily transient and self-limiting with no negative long-term consequences reported 5.

Mechanism of Action

Teplizumab binds to CD3 on T lymphocytes and modulates the autoimmune attack through:

• Partial agonistic signaling and deactivation of pancreatic beta cell autoreactive T lymphocytes 2
• Increased proportion of regulatory T cells 2
• Increased exhausted CD8+ T cells (specifically KLRG1+TIGIT+CD8+ T cells) 4
• Internalization of the teplizumab/CD3 complex from T-cell surfaces 2

This mechanism targets the root autoimmune process rather than merely treating symptoms 5, 6.

Critical Clinical Pitfalls to Avoid

Do not use teplizumab in:

• Patients with Stage 3 (symptomatic) type 1 diabetes already diagnosed—the FDA approval and evidence base specifically target Stage 2 disease 1, 2
• Patients under 8 years of age—safety and efficacy not established in this population 1, 2
• Settings without trained personnel to manage infusion reactions 1, 3

Do not delay treatment in eligible Stage 2 patients waiting for "perfect" genetic markers—the overall benefit is substantial even in patients without optimal predictive markers 1, 4.

Otelixizumab Status

Otelixizumab, another anti-CD3 monoclonal antibody, showed promise in early studies but is not FDA-approved and is not available for clinical use 7. While it demonstrated benefits in recent-onset type 1 diabetes in Phase II trials, it did not advance to approval 7. Teplizumab remains the only clinically available antibody therapy 1.

Screening and Identification of Candidates

Screening programs to identify Stage 2 patients:

• TrialNet (www.trialnet.org) in the U.S. 1
• Fr1da and GPPAD programs (www.gppad.org) in Europe 1
• Screening focuses on relatives of type 1 diabetes patients and general population children 1

Testing for multiple islet autoantibodies coupled with education about diabetes symptoms and close follow-up enables earlier diagnosis and prevents diabetic ketoacidosis 1.

Counseling Points for Patients and Families

Patients receiving teplizumab should understand:

• Treatment delays but does not prevent type 1 diabetes—median delay is approximately 2 years 1, 4
• Continued monitoring for progression to Stage 3 diabetes remains essential 1
• Recognition of diabetes symptoms (polyuria, polydipsia, weight loss) is critical to prevent DKA 1
• Transient side effects (rash, lymphopenia) are expected and manageable 1