AT-1501 + Islet Cell Transplant for Type 1 Diabetes

Overseen By Piotr Witkowski, MD PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Chicago

Must be taking: Insulin

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Obesity, Hypertension, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

9 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those currently on certain treatments like systemic steroids or immunosuppressive drugs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug AT-1501 for Type 1 Diabetes?

Research shows that AT-1501, an anti-CD40L antibody, helps in the long-term survival of transplanted islet cells in nonhuman primates, which suggests it could be effective for Type 1 Diabetes. It has been engineered to reduce side effects and has shown promise in promoting the survival and function of transplanted organs. ^{1 2 3 4 5}

Is AT-1501 (Tegoprubart) safe for use in humans?

AT-1501 (Tegoprubart) has been engineered to reduce the risk of blood clotting issues seen with similar treatments and has shown safety in nonhuman primate studies, supporting its potential for safe use in humans. ^{1 2 4 5 6}

What makes the drug AT-1501 unique for treating Type 1 Diabetes?

AT-1501 is unique because it is an anti-CD40 ligand monoclonal antibody designed to prevent islet transplant rejection without causing thromboembolic complications, which were a problem with previous similar treatments. It works by blocking a specific immune pathway, helping the transplanted cells survive longer and function better. ^{1 2 4 5 6}

What is the purpose of this trial?

AT-1501 is a monoclonal antibody. Antibodies are Y-shaped proteins that are produced naturally by the subject's immune system to attack and fight foreign substances that cause illness. Monoclonal antibodies are man-made proteins manufactured to serve as substitute antibodies to fight diseases. Monoclonal antibodies can restore, enhance, or mimic (copy) the immune system's attack process; they can also tone down the immune system. AT-1501 is thought to work by dampening down the immune system so that it will be less likely to attack the transplanted cells. For other types of transplants, like kidney, a drug called a calcineurin inhibitor is usually used to prevent rejection. That class of drugs can be toxic to islet cells. AT-1501 is an experimental agent that is anticipated to prevent rejection without harming the islet cells.

Research Team

John Fung, MD PhD

Principal Investigator

University of Chicago

Eligibility Criteria

Adults aged 18-65 with brittle Type 1 Diabetes Mellitus, diagnosed for over 5 years and onset before age 40. Participants must have had at least three severe hypoglycemic episodes in the past year not due to missed meals or dosing errors, an HbA1c level between 7.0% and 9.5%, no C-peptide response after a meal test, impaired awareness of hypoglycemia, and be under regular diabetes management.

Inclusion Criteria

Patients with Coronavirus Disease 2019 (COVID-19) Polymerase chain reaction (PCR) negative test result

Ability to provide informed consent

Able to comply with study procedures, including the requirement to utilize continuous glucose monitoring (CGM)

Exclusion Criteria

Blood pressure: systolic blood pressure (SBP) >140 mmHg or diastolic blood pressure (DBP) >90 mmHg

Persistent elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than 3 times the upper limit of normal (ULN); elevation of total bilirubin >1.5 ULN

Baseline Panel-reactive Antibody (PRA) over 20%

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Islet Cell Transplantation

Participants undergo islet cell transplantation using a catheter guided by X-rays and ultrasound

1 week

1 visit (in-person)

Treatment

Participants receive AT-1501 in combination with standard immunosuppressive medicines to prevent rejection of transplanted islet cells

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• AT-1501

Trial Overview The trial is testing AT-1501, a man-made antibody designed to suppress the immune system without harming transplanted islet cells that produce insulin. This could help prevent the body from rejecting these cells in patients with T1D who receive cell transplants to manage their condition.

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

Cure Alliance

Collaborator

Trials

1

Recruited

9+

Juvenile Diabetes Research Foundation

Collaborator

Trials

237

Recruited

142,000+

Findings from Research

A chimeric CD40-specific monoclonal antibody (Chi220) was effective in promoting the survival of transplanted neonatal porcine islets in diabetic macaques, with five out of six recipients achieving insulin independence for a median of 59 days.

This study suggests that targeting the CD40 pathway may be a promising alternative to the CD154 pathway for improving islet xenotransplantation outcomes, with no observed thromboembolic complications, indicating a potentially safer approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Thompson, P., Cardona, K., Russell, M., et al.[2023]

The monoclonal antibody AT-1501 (Tegoprubart) effectively promotes long-term survival of islet and kidney transplants in nonhuman primate models, demonstrating its potential as a safe immunosuppressive agent.

AT-1501 treatment resulted in improved metabolic outcomes, such as higher C-peptide levels and weight gain, along with a lower incidence of cytomegalovirus reactivation compared to traditional immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. Anwar, IJ., Berman, DM., DeLaura, I., et al.[2023]

In a study involving diabetic rhesus macaques, the combination of CTLA4Ig with a CD40 blockade regimen led to long-term survival of transplanted islets and was well tolerated, indicating its potential as a safer immunosuppressive strategy.

The addition of CTLA4Ig effectively prevented the formation of donor-specific antibodies (DSA), which are a major barrier to successful islet transplantation, suggesting that this approach could improve outcomes in clinical settings without relying on traditional CD154 blockade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. Badell, IR., Russell, MC., Cardona, K., et al.[2023]

The novel monoclonal antibody 2C10 effectively inhibited T cell-dependent antibody responses in rhesus macaques without causing significant depletion of peripheral B cells, indicating a safer immunosuppression strategy.

In a transplantation model, 2C10 significantly prolonged islet graft survival compared to standard treatments, highlighting its potential as an effective therapy for preventing alloimmune responses in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel monoclonal antibody to CD40 prolongs islet allograft survival. Lowe, M., Badell, IR., Thompson, P., et al.[2023]

The human CD40-specific monoclonal antibody (mAb) 3A8 significantly prolonged islet allograft survival in a rhesus macaque model without depleting B cells, suggesting its potential as a safer alternative for preventing transplant rejection.

Unlike previous strategies that relied on blocking CD154, the efficacy of 3A8 indicates that complete blockade of CD40 binding or cellular depletion is not necessary for effective allograft protection, paving the way for further development of CD40-targeted therapies in human transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates. Badell, IR., Thompson, PW., Turner, AP., et al.[2023]

ASKP1240, a fully human anti-CD40 monoclonal antibody, significantly prolonged the survival of pancreatic islet transplants in cynomolgus monkeys, with graft survival times extending beyond 600 days compared to control groups that rejected transplants within 9 days.

The treatment with ASKP1240 did not result in serious adverse events and effectively abolished anti-donor cellular responses and antibodies, suggesting it could be a safe and effective option for immunosuppression in clinical islet transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates. Watanabe, M., Yamashita, K., Suzuki, T., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

A novel monoclonal antibody to CD40 prolongs islet allograft survival. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

ASKP1240, a fully human anti-CD40 monoclonal antibody, prolongs pancreatic islet allograft survival in nonhuman primates. [2023]