Profile | Islex Therapeutics

Company Profile

Islex Therapeutics, a biotechnology startup spun off from Johns Hopkins University, is dedicated to developing precision therapies for patients with type 1 diabetes, latent autoimmune diabetes in adults (LADA) and severe type 2 diabetes. The commonality among these insulin-dependent diabetes lies in the destruction of beta cells in the pancreatic islets, the sole source of insulin production in the body. Islex Therapeutics is a pioneer in the development of the world's only drug delivery platform specifically designed for targeted beta cell therapies. This groundbreaking platform is anchored in the discovery of an islet-specific cell-surface autoantigen, ZnT8. By harnessing the natural islet-homing ability of a cell-surface ZnT8 autoantibody, Islex Therapeutics re-engineers it to guide antibody-conjugated therapeutics to islets, enhancing drug efficacy within the islet microenvironment while minimizing off-target toxicity. Currently, the company is focused on preclinical development of islet-targeted immunoregulatory and regenerative therapeutics on a proprietary drug delivery platform, validating therapeutic candidates for future clinical testing.

Unmet Medical Needs: Currently, there is no medication available to sustainably halt autoimmune destruction or provide a lasting arrest in the irreversible deterioration of beta cells in advanced-stage diabetes.

Diabetes encompasses a spectrum of metabolic disorders, ranging from type 1 diabetes (T1D), latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Regardless of their diverse etiologies, advanced-stage diabetes is characterized by a severe loss of the insulin-producing beta cells, necessitating exogenous insulin injections.

Insulin replacement therapy is the cornerstone treatment for advanced-stage diabetes. However, in cases of severe beta cell loss, exogenous insulin alone is insufficient to maintain euglycemia. The current last-resort treatment for diabetes is pancreas transplantation, but it faces limitations due to the scarcity of donor organs and the requirement for life-long immunosuppression.

Emerging treatments include stem cell transplants, regeneration pharmacotherapies and artificial pancreas systems. These approaches encounter challenges such as the risk of abnormal cell growth, off-target toxicity and suboptimal glycemic regulation. The pursuit of safe and effective treatments for advanced-stage diabetes remains a formidable undertaking.

Journey of our discoveries

The molecular recognition of an islet cell surface marker enables islet-targeted therapies precisely at the disease site.

Cell-surface membrane proteins provide entry points for therapeutics and biomarker discovery. ZnT8, a zinc-specific transporter, is specifically expressed in the pancreatic islet. Our research has identified ZnT8 as a dynamic cell-surface marker for beta cells1.

We have discovered and developed a ZnT8-targted drug delivery platform for pancreatic islets2.

We have demonstrated efficacy and safety of a cell-surface ZnT8 autoantibody in a mouse model of T1D3.

We are developing surrogate endpoints to facilitate clinical evaluation of ZnT8-mediated therapies4,5.

References

1. Huang, Q., Merriman, C., Zhang, H., and Fu, D. (2017) Coupling of Insulin Secretion and Display of a Granule-resident Zinc Transporter ZnT8 on the Surface of Pancreatic Beta Cells. J Biol Chem 292, 4034-4043

2. Guo, Z., Kasinathan, D., Merriman, C., Nakayama, M., Li, H., Li, H., Xu, C., Wong, G. W., Yu, L., Golson, M. L., and Fu, D. (2023) Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for In Vivo beta-Cell Imaging and Islet-Specific Therapies. Diabetes 72, 184-195

3. Kasinathan, D., Guo, Z., Sarver, D. C., Wong, G. W., Yun, S., Michel, A., Yu, L., Golson, M. L., and Fu, D. (2023) Cell-surface ZnT8 antibody prevents and reverses autoimmune diabetes in mice. Diabetes In review

4. Gu, Y., Merriman, C., Guo, Z., Jia, X., Wenzlau, J., Li, H., Li, H., Rewers, M., Yu, L., and Fu, D. (2021) Novel autoantibodies to the beta-cell surface epitopes of ZnT8 in patients progressing to type-1 diabetes. J Autoimmunity 122, 102677

5. Wan, H., Merriman, C., Atkinson, M. A., Wasserfall, C. H., McGrail, K. M., Liang, Y., Fu, D., and Dai, H. (2017) Proteoliposome-based full-length ZnT8 self-antigen for type 1 diabetes diagnosis on a plasmonic platform. Proc Natl Acad Sci U S A 114, 10196-10201

ZnT8 biotechnologies

Our scientific discovery is driven by technological innovation. ZnT8 is an important yet intractable membrane protein for biochemical characterization, intracellular tracking and therapeutic targeting. These technical barriers have been summoned by a suite of novel technologies highlighted by the following issued, granted and provisional patents.

Pipeline

Our pipeline of precision therapies targets T1D, LADA and severe T2D with the mAb43 monotherapy and combination therapies with Iset-directed antibody-drug conjugates (ADCs). These multifunctional biologics comprise four interconnected modules:

1. An islet-homing module that guides systematically administered ADCs to pancreatic islets,

2. A mitogenic module that stimulates adult beat cell growth.

3. A cell-surface masking module that provides a protective shield against autoimmune attacks in T1D.

4. A stress-suppressing module that safeguards β-cells from stress-induced apoptosis in T2D.