Humanized Anti-ACTH Antibodies for Selective Epitope Targeting
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Solution Overview
Problem
Existing anti-ACTH antibodies interact with non-specific regions of ACTH, leading to unintended effects such as hyperpigmentation and elevated steroid hormone levels, which are not effectively addressed in conditions like Cushing's disease and hyperaldosteronism.
Innovation Solution
Development of human, humanized, or chimerized anti-ACTH antibodies and fragments that specifically target unique epitopes on ACTH, avoiding interaction with ACTH 1-13 and ACTH 18-39, and are designed to inhibit ACTH activation of melanocortin receptors, thereby reducing cortisol and aldosterone secretion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-ACTH antibodies are used to treat ACTH-related disorders, then ACTH binding occurs, but unintended effects such as hyperpigmentation and elevated steroid hormone levels occur due to non-specific interaction with ACTH regions
Solution Approach 1:
The patent applies local quality by designing antibodies that target specific local regions (epitopes) of the ACTH molecule. The antibodies are engineered to bind exclusively to the central region of ACTH (amino acids 6-24), while deliberately avoiding the N-terminal region (amino acids 1-13) that triggers melanocortin-1 receptor activation and hyperpigmentation. This localized binding approach maintains therapeutic efficacy on ACTH while eliminating harmful side effects.
Solution Approach 2:
The patent segments the ACTH molecule into distinct functional regions and targets only the therapeutic-relevant segment. By focusing antibody binding on the central region (amino acids 6-24) that is responsible for ACTH's corticotropin activity, the invention separates the therapeutic effect from the harmful pigmentation effect, which arises from N-terminal region interaction.
2Reliability
If antibodies target ACTH to reduce cortisol and aldosterone levels, then therapeutic benefit is achieved, but interaction with ACTH 1-13 and/or ACTH 18-39 regions causes unintended effects
Solution Approach 1:
The invention implements local quality by confining antibody binding to a specific local epitope within the ACTH molecule (amino acids 6-24). This localized targeting ensures that the antibodies exert their therapeutic effect on cortisol and aldosterone regulation while avoiding interaction with the N-terminal region (amino acids 1-13) that would cause harmful side effects.
Solution Approach 2:
The patent uses the central region of ACTH (amino acids 6-24) as an intermediary target that mediates the therapeutic effect without triggering harmful responses. By directing antibodies to this intermediate region rather than the N-terminal region, the invention creates a selective binding pathway that achieves therapeutic goals while bypassing harmful interactions.
3Adaptability or versatility
If existing anti-ACTH antibodies bind to multiple regions of ACTH, then broad coverage is achieved, but selectivity for therapeutic epitopes is reduced leading to side effects
Solution Approach 1:
The patent applies local quality by designing antibodies with highly specific binding characteristics for a localized epitope on ACTH. Rather than creating antibodies that bind broadly to multiple regions, the invention engineers antibodies that concentrate their binding affinity on the specific therapeutic region (amino acids 6-24), achieving precision in epitope selection while maintaining effective therapeutic coverage.
Data Source
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AI summary
The present invention is directed to antibodies and fragments thereof having binding specificity for ACTH. Embodiments of this invention relate to the binding fragments of antibodies described herein, comprising the sequences of the VH, VL and/or CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates anti-ACTH antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention further contemplates methods of making said anti-ACTH antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-ACTH antibodies and binding fragments thereof for the diagnosis, assessment, prevention and treatment of diseases and disorders associated with ACTH, such as CAH, FGD, Cushing's Disease, Cushing's Syndrome, Parkinson's disease, obesity, diabetes, sleep disorders, depression, anxiety disorders, cancer, muscle atrophy, hypertension, hyperinsulinemia, cognitive dysfunction, Alzheimer's disease, galactorrhea, stress related conditions, cardiac conditions, metabolic syndrome, hyperaldosteronism, Conn's syndrome and familial hyperaldosteroni sm.