Antibody Drug Conjugates for Targeted Glucocorticoid-PD1 Modulation
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Solution Overview
Problem
Existing therapies for modulating immune responses, particularly those involving glucocorticoids, lack specificity and efficacy in targeting specific tissues or cell types, leading to inadequate treatment of conditions such as inflammation, autoimmune diseases, and cancers.
Innovation Solution
The development of antibody drug conjugates that target innate lymphoid cells, specifically NCR1+ innate lymphoid cells, using glucocorticoid receptor agonists or antagonists to modulate the glucocorticoid-PD1 pathway, thereby regulating immune responses to prevent tissue damage while maintaining viral clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammatory conditions, then anti-inflammatory effects are achieved, but tissue-specific and cell-specific therapeutic precision is lost due to pleiotropic actions on multiple cellular targets
Solution Approach 1:
The patent applies local quality by conjugating glucocorticoid agonists or antagonists to antibodies that specifically bind to surface markers on target cells (e.g., CD3, CD19, CD20, CD52, PD1, CTLA4). This ensures the therapeutic agent is delivered specifically to desired cell types in specific tissues, achieving both therapeutic efficacy and cellular precision simultaneously.
Solution Approach 2:
The patent uses antibody-drug conjugates as intermediaries between the glucocorticoid therapeutic agent and the target cells. The antibody component acts as a mediator that guides the glucocorticoid to the specific cellular target, enabling precise delivery while maintaining the anti-inflammatory or immunomodulatory effects of the glucocorticoid.
2Reliability
If conventional immunosuppressive therapies are used, then immune response modulation is achieved, but differentiation between pathogen elimination and collateral tissue damage control is lost
Solution Approach 1:
The patent enables local quality by targeting glucocorticoid therapy to specific cell populations involved in either pathogen elimination or tissue damage. By selecting appropriate surface markers and glucocorticoid agonists/antagonists, the therapy can selectively modulate harmful immune responses while preserving protective immune functions in specific tissues.
Solution Approach 2:
The patent applies parameter changes by using different glucocorticoid agonists or antagonists with varying potencies and durations of action, combined with different antibody targets. This allows fine-tuning of the immune response modulation to achieve the desired balance between pathogen elimination and tissue protection.
3Adaptability or versatility
If glucocorticoid receptor activity is modulated systemically, then broad immunoregulatory effects are achieved, but cell lineage-specific molecular mechanisms remain poorly understood and ineffective
Solution Approach 1:
The patent achieves local quality by conjugating glucocorticoid modulators to antibodies that recognize cell lineage-specific surface markers. This enables selective targeting of particular immune cell populations (e.g., T cells, B cells, NK cells) while maintaining broad immunoregulatory coverage through the choice of different antibody-antigen pairs and glucocorticoid variants.
Solution Approach 2:
The patent applies universality by creating a platform technology where the same glucocorticoid conjugate methodology can be applied to target multiple different cell types by simply changing the antibody component. This universal approach allows systematic study and exploitation of cell lineage-specific molecular mechanisms across different immune cell populations.
Data Source
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AI summary
The present invention relates to methods for modulating innate lymphoid cell activity, antibody drug conjugates and uses in therapy. The inventors showed in a model of murine cytomegalovirus infection, that glucocorticoid receptor expression in innate lymphoid cells plays an essential early role in regulating host protection against inflammation-induced tissue damage. Mechanistically, they demonstrated for the first time that endogenous glucocorticoids produced shortly after infection promote the expression of the immune checkpoint PD1 on the surface of natural killer cells. This glucocorticoid-PD1 pathway acts to limit the production of interferon-γ by NK cells. The modulation of the glucocorticoid-PD1 pathway in order to increase or decrease the activity of ILCs would permit to treat either cancers and infectious diseases or autoimmune and inflammatory diseases. In particular, the present invention relates to a method of modulating innate lymphoid cell activity which comprises modulating the activity of glucocorticoid receptor.