Objective
In previous projects supported by T1D Breaktrough and the Helmsley Trust, our team has discovered and validated a promising way to detect beta cells inside the body, using a marker called DPP6 and the small camel antibody 4hD29. The goal now is to go into “prime time”, turn this into a safe, medical-grade probe so that we can finally “see” beta cells in people with type 1 diabetes. This would be a major breakthrough for understanding the disease evolutions and testing new treatments.
Background Rationale
There are presently no reliable ways to measure the number of insulin-producing cells inside a person’s pancreas, and without a way to measure them directly it’s very hard to follow how the disease develops or test new treatments to preserve beta cell mass in T1D. To address this major unmet need, we need to find specific surface “markers” that are unique to beta cells. These markers can then be used with medical imaging techniques (like PET scans) to measure beta cell mass inside the body.
In earlier projects, our team identified two promising markers found on the surface of beta cells: DPP6 and FXYD2γa. Both are patented and published. Of these, DPP6 is the most advanced for moving into real-world testing. We created a small, specialized camel antibody (called 4hD29; these special antibodies have 10% of the size of a human antibody, making them particularly suitable for imaging) that attaches only to DPP6. In experiments funded by the Helmsley Trust, we showed that 4hD29 can be used to detect human beta cells transplanted into mice using PET scans—the same method planned for human trials. Importantly, 4hD29 attached to beta cells but not to other tissues, showing it is highly specific.The next step, and the aim of the present project, is to produce a clinical-grade version of 4hD29, test its safety, and study how it behaves in the body in pre-clinical models.
Description of Project
Type 1 diabetes is a chronic autoimmune disease characterized by pancreatic islet inflammation and progressive beta cell loss. There are presently no reliable ways to measure the number of insulin-producing cells inside a person’s pancreas, and without a way to measure them directly it’s difficult to follow how the disease develops or test new treatments. To address this major unmet need, we need to find specific surface “markers” that are unique to beta cells. These markers can then be used with medical imaging techniques (like PET scans) to measure beta cell mass inside the body.
In earlier projects, our team identified two promising markers found on the surface of beta cells: DPP6 and FXYD2γa. Both are patented and published. Of these, DPP6 is the most advanced for moving into real-world testing. We created a small, specialized camel antibody (called 4hD29; these special antibodies have 10% of the size of a human antibody, making them particularly suitable for imaging) that attaches only to DPP6. In experiments funded by the Helmsley Trust, we showed that 4hD29 can be used to detect human beta cells transplanted into mice using PET scans—the same method planned for human trials. Importantly, 4hD29 highlighted beta cells but not other tissues, showing it is highly specific. The next step, and the aim of the present project, is to produce a clinical-grade version of 4hD29, test its safety, and study how it behaves in the body. This would allow the first human trial of beta cell imaging with these tools. If results with DPP6 don’t work out, we will also develop a similar small camel antibody against FXYD2γa as a backup option.
Goals of the Project:
Aim 1: Preparing for the first human trial of the DPP6 marker
• Produce medical-grade (GMP-certified) versions of 4hD29.
• Confirm it still targets only beta cells using human tissue samples.
• Label it with a safe radioactive marker (Gallium-68) so it can be detected with PET scans.
• Test it in monkeys to confirm results seen in earlier rat studies.
• Perform safety studies in rats to make sure it has no harmful effects at doses 100-fold higher than what would be used in people.
• Write the required regulatory documents for approval.
• Submit everything to the European Medicines Agency for permission to begin the human trial.
Aim 2: Further lab testing of the new probe against FXYD2γa
• Test for any possible toxic effects in human beta cells, making sure they keep working properly and continue releasing insulin and preserving their differentiated state.
• Study how specifically and how quickly the probes attach to beta cells compared with other tissues.
• Test it in mice with implanted human beta cells to check both safety and function.
In summary, our team has discovered and validated a promising way to detect beta cells inside the body, using a marker called DPP6 and the small antibody 4hD29. The goal now is to turn this into a safe, medical-grade probe so we can finally “see” beta cells in people with type 1 diabetes. This would be a major breakthrough for understanding the disease and testing new treatments.
Anticipated Outcome
The anticipated outcome of the present project is to produce a clinical-grade version of 4hD29 (a camel small antibody that binds DPP6), test its safety, and study how it behaves in the body in pre-clinical models. This will allow the first human trial of beta cell imaging in 10 individuals, 5 normoglycemic and 5 affected by long-term T1D and not producing detectable insulin, as measured by C-peptide. As a backup option, we will also develop a second small camel antibody, this time against FXYD2γa, another beta cell biomarker discovered by our team.
Relevance to T1D
Being able to measure beta cell mass in vivo will have two immediate and beneficial effects: 1. It will allow to follow up the evolution of the disease – particularly the progressive beta cell loss – in both individuals at risk for T1D and in the first year post-diagnosis; 2. It will enable verifying whether novel therapies prevent beta cell loss or restore the beta cell mass lost in T1D. Furthermore, and another goal of our team, it will open the door for future projects aiming to deliver therapeutic cargo specifically to the beta cells.