AN IMMUNE TARGETED, NON-TOXIC CORTICOSTEROID FOR THE TREATMENT OF SEVERE AUTOIMMUNE DISEASE
Abstract: OP0049
Authors: J. Rothstein et al.
Key content:
Glucocorticoids (GC) are a class of drugs with broad range anti-inflammatory and immunosuppressive activities making them the most potent anti-inflammatory drugs. However, chronic or high dose systemic exposure consistently leads to grievous dose limiting toxicities in multiple organs including brain, liver and bone. Targeting GC to immune cells will solve this problem as toxicity mostly occurs in non-immune tissues and cells that are unnecessary for therapeutic efficacy.
The objective of INX200 is to give patients a non-toxic glucocorticoid that provides anti-inflammatory efficacy without any glucocorticoid toxicity in a once-per month injection. INX200 is a fully humanized immune-targeting monoclonal antibody with silent Fc domain and conjugated through a cleavable linker to budesonide. Validation experiments were conducted using human target knock-in mice, mouse surrogate antibodies and non-human primates in various inflammation and chronic disease models.
In this animal studies INX200 targets both lymphoid and myeloid cells with minimal off-target activity outside the immune compartment. This translates to reduced toxicity when compared to free GC as measured by the lack of impact on the Hypothalamic-Pituitary-Adrenal axis (no changes in corticosterone levels) and bones (no changes in GC- activated transcription) both in mice and non-human primates.
INX200 rapidly internalizes allowing for robust and efficient uptake into immune cells which results in therapeutic equivalence to free GC at 1/10th of the dose. One dose of INX200 also leads to substantially longer exposure (>3 weeks) when compared to free GC (<24h) both in mice and non-human primates. Additionally, INX200 was in both acute and chronic inflammation models therapeutically as efficacious as free GC.
Relevance:
Based on these data from animal studies in various inflammation and chronic disease models, INX200 seems to be a very interesting new approach to separating the good effect of glucocorticoid therapy from the possible side effects. INX200 retained in these studies all the efficacy/potent therapeutic activities of GC but with little to no side effects. The successful targeting of GC to the immune system with the sparing of non-hematopoietic toxicities offers a transformative advance in GC-based drugs for the treatment of severe, chronic inflammatory diseases.
