POS0666 IMMUNE-TARGETED GLUCOCORTICOID ADC FOR THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES

Background: Glucocorticoids (GCs) are the most versatile and efficacious anti-inflammatory drugs rheumatologists have available for patients. Unfortunately, prolonged systemic GC exposure also leads to unacceptable toxicities, which have resulted in reduced GC use and dependence on biologics that may be safer but are not more effective. Indeed, over several decades, cytokine biologics and JAK inhibitors have emerged, but these, too, have associated immunotoxicity and are not universally efficacious. Targeted delivery of GCs to immune cells minimizes exposures to other organ systems thus preserving the clinical efficacy of GCs and mitigating the systemic toxicities that preclude their broader, more prolonged use. Objectives: We designed an antibody-drug conjugate (ADC) that minimizes systemic toxicities by selectively delivering a GC payload via a linked antibody. This new ADC, LFD-200, has high affinity for VISTA, a protein that is preferentially expressed on immune cells. Targeting VISTA enables rapid delivery of a potent glucocorticoid to myeloid and T cells, plasma cells, and endothelial cells. Modifying the GC payload and targeting the rapidly internalizing VISTA protein avoids long serum exposure, increases potency, and leads to long immune exposure with greater efficacy than conventional corticosteroids in disease models. Methods: The ADC LFD-200 was created by conjugating a potent small molecule GC via a linker to a highly selective antibody that targets VISTA. Proof-of-concept experiments using subcutaneously administered LFD-200 were conducted in human primary cells, and multiple mouse disease models of acute and chronic inflammation. Tissue exposures were measured by mass spectrometry (MS) in non-human primates (NHPs) and by immunohistochemistry (IHC) using a proprietary antibody to the payload in mouse studies. In preclinical toxicity studies, NHPs were injected every other week with LFD-200 for up to 4 weeks at high dose. Results: LFD-200 increases GC efficacy by targeting immune cells. The robust and efficient uptake of the ADC into immune cells results in long intracellular pharmacokinetics that leads to a significant and sustained treatment effect in mouse models of acute and chronic disease when dosed weekly. LFD-200 exposures were highest in immune tissues in NHP studies where animals were given LFD-200 at 10 mg/kg. MS analyses showed that negligible concentrations of drug were detected in serum and other major organs such as liver and lung at 24 hours post dose, and at day 8, payload was detected mainly in immune tissues. In mouse IHC studies where LFD-200 was dosed at 10 mg/kg, LFD-200 payload was detected in T cells, myeloid cells and high endothelial venules in lymph nodes and spleen. LFD-200 treatment showed no evidence of systemic GC toxicity. Preclinical toxicity studies in NHPs showed that LFD-200, even at a high dose (250 mg/kg), caused no systemic toxicity, including no impact on the hypothalamic-pituitary-adrenal axis (Figure 1). The LFD-200 manufacturing process has been transferred and scaled to support IND-enabling studies. The scaled material recapitulated initial target binding and efficacy research data. A subcutaneous formulation of LFD-200 has been developed. It has shown a favorable tissue distribution profile in NHPs, allowing for more convenient dosing options. Conclusion: Non-clinical experiments indicate that the ADC LFD-200 demonstrated potent anti-inflammatory properties in immune tissues while having minimal exposures in non-immune tissues, including no impact on cortisol even at high doses. LFD-200 will enter the clinic for evaluation in healthy volunteers and patients with a prevalent autoimmune disease in 2025. The successful targeting of GCs to the immune system with the sparing of non-immune toxicities offers a new way to treat autoimmune and inflammatory conditions across various medical disciplines, including rheumatology, gastroenterology, pulmonology, and dermatology. Figure 1 Repeated high doses of LFD-200 do not impact cortisol levels in NHPs . Male and female cynomolgus macaques received a high dose (250 mg/kg) of LFD-200 subcutaneously on days 1, 15, and 29. Cortisol levels were measured pre-dosing on the same days (n=2 for the vehicle and n=4 for LFD-200). REFERENCES: NIL . Acknowledgements: We would like to thank all our consultants, advisors and CROs for help in designing and executing the non clinical studies described in this abstract. Disclosure of Interests: Jay Rothstein Lifordi, Amgen, ImmuNext, Catherine Carriere Lifordi, Kierstin Bell Lifordi, Maria Day Lifordi, Xin Huang Lifordi, Anna Kuta-Howe Lifordi, Nicholas Schwertner Lifordi, Irina Koroleva Lifordi, Novartis, Geoffrey Kuesters Lifordi, Margaret Weaver Lifordi, David Nichols Lifordi, Mathew McClure Lifordi. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.