Objective
The study proposed here will test the following:
• Loading capacity: Determine the maximum feasible amount of Tegoprubart that can be loaded into hydrogel microbeads, including scenarios using various approaches to concentrate the drug within the microbeads to eventually meet the weekly dosing target.
• Compatibility and formulation: Assess how Tegoprubart interacts with the hydrogel, including mixing, particle size, and bead formation.
• Release profiling: Generate in vitro release data up to about four weeks to see if the hydrogel enables extended or modulated release, informing future in vivo comparisons.
• Antibody integrity: Monitor structural quality over time, including the proportion of monomer, levels of aggregation, and potency, with samples analyzed by a designated third-party lab.
• Manufacturing relevance: Explore concentration ranges and volume considerations to support potential SC or SC-infusion administration, ensuring results align with clinical and commercial needs.
• Decision-making support: Produce data to guide internal formulation decisions, pharmacokinetic (PK) modeling, and planning for future in vivo studies, as well as CMC (chemistry, manufacturing, and controls) considerations.
Background Rationale
The development of Tegoprubart (formerly AT-1501) represents a significant shift in the effort to make islet cell transplantation a viable, long-term cure for Type 1 Diabetes (T1D). Traditionally, patients receiving donor pancreatic islets had to remain on lifelong immuno-suppressing drugs to prevent rejection. The standard of care has long relied on calcineurin inhibitors (CNIs), such as tacrolimus. However, tacrolimus presents a challenge for islet transplants. While the drug prevents the immune system from attacking the newly transplanted cells, it is also inherently toxic to those very beta-cell and often leads to kidney damage and neurological side effects along with failure of the transplant.
Tegoprubart takes a different approach. It is a humanized monoclonal antibody designed to inhibit the CD40/CD40L (CD154) costimulatory pathway. This pathway is critical between T-cells and other immune cells required to trigger an adaptive immune response. By blocking this signal, Tegoprubart prevents the activation of effector T-cells that would otherwise destroy the transplanted islets. Unlike earlier anti-CD40L candidates that failed due to blood-clotting risks, Tegoprubart is engineered with a mutated "Fc region" that avoids binding to platelets, significantly improving its safety profile. The outcome in a recent clinical evaluation of the drug showed that it maintained function of transplanted islets without tacrolimus and islet engraftment that was 3-5 times higher in patients given Tegoprubart. In this study, Likarda will trap the Tegoprubart within a hydrogel polymer that degrades slowly in the body, thus reducing the need for the initial daily injections.
Description of Project
This plan submitted here is a collaboration between Likarda, Inc., Eledon, and Breakthrough T1D (BT1D) to explore a new way to deliver Tegoprubart, a monoclonal antibody, under the skin (subcutaneously). The aim is to determine whether Likarda’s NovoSphere™ hydrogel encapsulation technology can enable much higher drug loading and a controlled, extended release, making weekly high-dose dosing feasible in a subcutaneous (SC) format.
Currently Tegoprubart treatment is IV and requires a large weekly dose (about 1,500 mg). Administering this amount subcutaneously in a practical volume is challenging. The study investigates whether hydrogel encapsulation can increase loading density and modulate release to support extended-release dosing. Likarda’s NovoSphere™ hydrogel polymers have previously shown the ability to encapsulate proteins, reduce initial burst release, and work with aqueous formulations. If successful, this could translate into a manufacturable, administration of Tegoprubart that lessens the patient burden.
Anticipated Outcome
Developing an extended-release (ER) or long-acting version of Tegoprubart would likely transform it from a clinical "breakthrough" into a practical, lifelong maintenance therapy for diabetes. While currently administered as a regular intravenous (IV) infusion in clinical trials, a formulation that allows for less frequent dosing (e.g., monthly or quarterly) could solve several hurdles in cell therapy. If Likarda's NovoSphere™ enables higher loading and controlled release without compromising antibody quality, Tegoprubart could move toward a viable, less-frequent dosing strategy, potentially simplifying administration and improving patient experience. The results would also inform future animal studies required to verify the extended-release of the drug, as well as practical manufacturing strategies.
One of the most critical benefits of an extended release version of Tegoprubart would be the maintenance of a constant therapeutic window. Traditional dosing can lead to "peaks and troughs" in drug concentration. By maintaining a steady level of the antibody, the CD40/CD40L pathway would remain permanently "shuttered," preventing any "leakage" or transient immune activation that could cause chronic, low-grade rejection of the fragile islet cells.
The second important aspect of an extended-release Tegoprubart would be the protection Against beta-cell exhaustion. Islet cells are notoriously sensitive to environmental fluctuations. Because Tegoprubart avoids the toxicity associated with current drugs like tacrolimus, an extended-release version would provide a more permanent shield. This stable environment would allow transplanted stem-cell-derived islets to mature and engraft more effectively, leading to higher rates of long-term insulin independence.
Finally, with any long-term therapy, the risk of a patient skipping a dose is reduced. For some drugs even missing a single dose can lead to graft failure. A long-acting formulation (such as a 3-month depot injection) reduces the burden on the patient.
Relevance to T1D
As stated above Tegprubart has already been shown to improve the outcomes of patients receiving islet cell transplants to treat T1 diabetes. In addition to the improved patient experience with an extended release drug, the impact of islet transplants with a higher rate of success would also lower healthcare costs for treating people with T1 diabetes. Extending the life of a single islet transplant would save millions in down stream care and make this life-saving therapy available to a larger number of people, including those in underserved areas who cannot travel to major transplant centers frequently.